Multi-putty bone hemostatic and adhesive compositions for use in methods of installing and securing surgical hardware in bones

ABSTRACT

Provided herein are bone hemostatic and adhesive compositions for use in surgical procedures comprising a variety of disclosed particles. Also provided are related compositions, including surgical hardware, surgical kits and packages, as well as methods of making and using the compositions.

RELATED APPLICATIONS

The application claims priority to U.S. Patent Application No.63/143,172 filed Jan. 29, 2021, and U.S. Patent Application No.63/298,439 filed Jan. 11, 2022, the contents of which are hereinincorporated by reference in their entirety.

FIELD OF THE INVENTION

The present disclosure relates to multi-putty bone hemostatic andadhesive compositions for use in methods of surgery comprising drilling,installing fenestrated and non-fenestrated surgical hardware into ornear surgical sites in bones. The present disclosure also relates to thefield of medical implants, optionally settable, implantable compositionsfor medical use in tissue hemostasis, repair and reconstruction.

BACKGROUND

Biodegradable polymers have become increasingly important for a varietyof biomedical applications including biomedical implants, such asstents, and coatings applied to those implants, tissue engineeringscaffolds, and soft-tissue adhesives. Segmented polyurethane elastomersin particular have come into wide use as biomaterials due to theirsuperior mechanical properties and chemical versatility. PCTInternational Application Publication No. WO 2004/009227 describescertain degradable polyurethane compositions for use as tissueengineering scaffolds. U.S. Pat. No. 6,306,177 (Felt et al.) describescurable polyurethane compositions comprising a plurality of partscapable of being sterilized, stably stored, and mixed at the time of usein order to provide a flowable composition upon mixing that issufficiently flowable to permit it to be delivered to the body byminimally invasive means. U.S. Patent Application Publication No.2005/0013793 (Beckman et al.) also describes degradable polyurethanesfor e.g., tissue engineering and particularly for bone repair andreplacement. U.S. Pat. No. 4,829,099 (Fuller et al.) describes certainabsorbable polyisocyanates for use as surgical adhesives. U.S. Pat. Nos.8,002,843 and 7,985,414 (Knaack et al.) describe a biodegradablepolyisocyante (such as lysine diisocyanate) with an optionallyhydroxylated biomolecule used to form a degradable polyurethane. U.S.Pat. No. 7,964,207 (Deslaurier et al.) describes osteoconductivepolyurethane compositions having mechanical properties consistent foruse in bone repair.

For certain applications, in addition to being biodegradable, it isadvantageous for a surgical implant to be moldable or formable, forexample to optimize its placement at the implant site and/or to fillvoids in hard or soft tissue at the site of implantation. U.S. Pat. Nos.8,431,147 and 8,282,953 (Warsaw Orthopedic, Inc) describe malleableimplants containing demineralized bone matrix (“DBM”). The “malleableimplant compositions” described in these patents contain a particulatesolid collagen material and a particulate solid DBM material along witha liquid carrier that comprises an aqueous gel of alginate. Alginate/DBMbased compositions are also described in U.S. Pat. No. 8,506,983 (WarsawOrthopedic, Inc). US 20130236513 (Guelcher et al.) describespolyurethane composites that, in some aspects, may be “processed” as areactive liquid that subsequently cures in situ to form a solidcomposite.

These and similar materials may contain polymers, ceramics, solid fattyacid and inorganic salts, dispersants, free radical scavengers andsolvents, as well as other optional additives such as catalysts,colorants, radiopaque agents, analgesics, anesthetics, antimicrobials,natural and recombinant growth factors and other bioactive peptides andproteins, antineoplastic and anti-inflammatory drugs, mineralized,partially demineralized and completely demineralized bone particles,adhesives, sealants, and porogens. See e.g., U.S. Pat. No. 7,989,000(Orthocon, Inc.), U.S. Pat. No. 8,603,528 (Abyrx, Inc.), and U.S. Pat.No. 9,314,547 (Abyrx, Inc.).

It is well known in the prior art to utilize surgical hardware e.g.,surgical screws for various bone reconstruction and repair surgeries.These procedures typically include inserting a bone screw into the bodyof the bone, and then connecting the Screw to either plates, rods orother surgical hardware for stabilization of the bone or bone fragmentsfor repair of fractures, deformations and other degenerative conditions.A major hurdle in this process is to properly secure the screw withinthe skeletal material of the bone. There exists a need for improvedSurgical Screws and bone adhesive and repair compositions, which canaddress these and other shortcomings of the installing surgical hardwarefor orthopedic and orthodontic surgeries.

There is a continuing need for improved surgical materials for use inhard and soft tissue repair.

SUMMARY OF THE INVENTION

The present disclosure provides compositions and methods relating tomoldable surgical implants suitable for use in hard and soft tissuerepair. It has now been discovered and disclosed in this application,that previously unclotted human pooled or autologous plasma, prescreenedfor pathogens, and optionally containing trehalose as a lyophilizationstabilizer, could be dried by lyophilization or simple evaporation andthen cold-ground or -milled and sieved into a uniform particulate formthat can be optionally added to moldable surgical implants, as describedherein, to provide exceptional bone, cartilage and soft tissuehemostasis and healing characteristics. As described in more detailinfra, anhydrous implants are preferred, so that the dry plasmaparticulate component remains active during ambient storage, preferablyin moisture resistant packaging.

Provided herein are mechanically hemostatic putty compositions includinga particulate component and a liquid component. For example, theparticulate component can include particles of previously unclottedlyophilized mammalian blood plasma. In some embodiments, the particlesof blood plasma are crosslinked (e.g., using genipin, heat, acarbodiimide, formaldehyde, glutaraldehyde, calcium, aluminum, chromium,iron, tin, magnesium and zinc salts of phosphate, sulfate, carbonate,bicarbonate, and/or any combinations thereof prior to lyophilization).In other embodiments, the particles are not crosslinked.

By way of non-limiting example, in any of the compositions describedherein, the particulate component may further contain a carboxylic acidsalt or a fatty acid ester of polyethylene glycol (e.g., a carboxylicacid salt can be selected from a calcium, magnesium, zinc, aluminum, orbarium salt of stearic acid; or a calcium, magnesium, zinc, aluminum, orbarium salt of palmitic acid and/or a fatty acid ester can bepolyethylene oxide stearate).

In any of the compositions described herein, the liquid component maycontain a block or random copolymer of ethylene oxide and propyleneoxide (e.g., the block copolymer may include one or more Pluronics),polyethylene oxide, triethylcitrate, acetyltriethylcitrate or anN-alkylpyrrolidone and combinations thereof. The liquid component canalso include a tocopherol or an ester thereof (e.g., tocopherolacetate). In some embodiments, the liquid component may additionally oralternatively contain triacetin and/or glycerol.

In preferred embodiments, the putty compositions described herein areanhydrous or substantially anhydrous.

By way of non-limiting example, the particulate component of thecompositions described herein can include a mono- or di- fatty acidester of a poly(alkyleneoxy)diol (e.g., polyethylene glycol (PEG)laurate, PEG stearate, PEG palmitate, and/or PEG behenate).

In any of the compositions described herein, the particulate componentmay further include a carboxylic acid salt (e.g., a calcium, magnesium,zinc, aluminum and/or barium salt of an even-numbered-carbon-atomhomologous series comprising lauric, myristic, palmitic, stearic,arachidic, and/or behenic acids (i.e., a calcium, magnesium, zinc,aluminum and/or barium salt of lauric acid; a calcium, magnesium, zinc,aluminum and/or barium salt of myristic acid; a calcium, magnesium,zinc, aluminum and/or barium salt of palmitic acid; a calcium,magnesium, zinc, aluminum and/or barium salt of stearic acid; a calcium,magnesium, zinc, aluminum and/or barium salt of arachidic acid; and/or acalcium, magnesium, zinc, aluminum and/or barium salt of behenic acid).

Any of the compositions described herein can additionally include aneffective amount of one or more additional therapeutic additives. By wayof non-limiting example, the one or more additional therapeuticadditives are selected from the group consisting of antimicrobialagents, analgesics, anesthetics, antineoplastic agents,anti-inflammatories, radiopaque agents, biocompatible colorants,osteopromotive agents, growth factors, chemical-based hemostats (e.g.,thrombin, fibrin, oxidized cellulose, styptic agents, protamine,chitosan, cross-linked, purified plant starch (e.g., Arista), and/orcombinations thereof), and/or combinations thereof.

In embodiments, any of the compositions described herein are sterile orsterilizable (i.e., the product, after mixing and packaging thecomponents, can be terminally sterilized).

Additionally (or alternatively), any of the compositions describedherein can be body absorbable.

Also provided are two putty settable bone hemostatic and adhesivecompositions, wherein the first putty (Putty A) includes apolyfunctional isocyanate, tocopheryl acetate, calcium phosphateparticles and a polyol and the second putty (Putty B) includes apolyfunctional isocyanate, calcium phosphate particles, at least onepolyol, a fatty acid salt and tocopheryl acetate. The first putty andthe second putty may be mixable together to form a mixed putty (PuttyC). Immediately after the two putties are thoroughly mixed to form amixed putty (Putty C), particles of previously unclotted, lyophilizedmammalian blood plasma may be added to the mixed putty and uniformlydistributed throughout the mixed putty. Also provided, therefore, is acomposition obtainable by mixing the first putty and the second putty toform a mixed putty, adding particles of previously unclotted,lyophilized mammalian blood plasma to the mixed putty and uniformlydistributing said particles throughout the mixed putty.

In any of these two-putty compositions, the first putty, the secondputty, or both the first putty and the second putty may include one ormore particulate materials selected from calcium sulfate, calciumphosphosilicate, sodium phosphate, calcium aluminate, and/or calciumphosphate and/or the second putty may include one or more ofhydroxyapatite, biomimetic carbonate apatite, demineralized bone, and/ormineralized bone.

In some embodiments, the first putty, the second putty, or both thefirst putty and the second putty includes one or more particulatematerials selected from a polyaryletherketone-based material, apolymethylmethacrylate-based material, and/or a tantalum- ortitanium-based filler.

In other embodiments, in any of these two putty compositions the firstputty, the second putty, or both the first putty and the second puttycomprises one or more particulate materials selected from calciumsulfate, sodium phosphate, calcium aluminate, strontium phosphate,calcium strontium phosphate, tricalcium phosphate, calciumpyrophosphate, and/or magnesium phosphate. By way of non-limitingexample, in these compositions, the second putty may include one or moreparticulate materials selected from hydroxyapatite, biomimetic carbonateapatite, biphasic calcium phosphate/hydroxyapatite, mineralized bonematrix, demineralized bone matrix, and/or glass ionomer. In someembodiments, the first putty, the second putty, or both the first puttyand the second putty can include one or more particulate materialsselected from absorbable phosphate glass, nonresorbable particulatemetallic materials (e.g., stainless steel powder, titanium powder,stainless steel nanoparticles, and/or titanium nanoparticles), and/ornonresorbable polymeric materials (e.g., polyurethane particles,polyureaurethane particles, polymethacrylic acid particles, andpolyarylether ketone particles (e.g., (polyether ketone (PEK), polyetherether ketone (PEEK), polyether ketone ketone (PEKK), polyether etherketone ketone (PEEKK) and/or polyether ketone ether ketone ketone(PEKEKK) particles)).

Any of the compositions described herein can additionally include aneffective amount of one or more additional therapeutic additives. By wayof non-limiting example, the one or more additional therapeuticadditives are selected from the group consisting of antimicrobialagents, analgesics, anesthetics, antineoplastic agents,anti-inflammatories, radiopaque agents, biocompatible colorants,osteopromotive agents, growth factors, chemical-based hemostats (e.g.,thrombin, fibrin, oxidized cellulose, styptic agents, protamine,chitosan, cross-linked, purified plant starch (e.g., Arista), and/orcombinations thereof), and/or combinations thereof.

Also provided herein is a composition comprising two putty components,the first putty (Putty A) including a dialkyl methylidene malonate esterand a poly(methylidenemalonate) ester and the second putty (Putty B)including a poly(methylidenemalonate) ester and particles of previouslyunclotted mammalian blood plasma. In some embodiments of thesecompositions, when thoroughly admixed, the first putty and the secondputty result in the formation of a third putty (Putty C) that is amoldable, settable surgical implant suitable for hard and soft tissuerepair.

In some embodiments, the second putty can include an effective amount ofone or more additional therapeutic additives (e.g., antimicrobialagents, analgesics, anesthetics, antineoplastic agents,anti-inflammatories, radiopaque agents, biocompatible colorants,osteopromotive agents, growth factors, chemical-based hemostats (e.g.,thrombin, fibrin, oxidized cellulose, styptic agents, protamine,chitosan, cross-linked, purified plant starch, and/or combinationsthereof), and/or combinations thereof).

Also provided is a composition comprising two putty components, thefirst putty (Putty A) including a cyanoacrylate ester at least one freeradical scavenger (e.g., hydroquinone, vitamin E acetate, beta caroteneand/or selenium acetate) and at least one acidifying agent (e.g., sulfurdioxide, sulfur trioxide and/or nitrogen dioxide) as anti-polymerizationstabilizers and the second putty (Putty B) including apoly(cyanoacrylate) ester and particles of previously unclottedmammalian blood plasma. In these compositions, when thoroughly admixed,the first putty and the second putty can result in the formation of athird putty that is a moldable, settable surgical implant suitable forhard and soft tissue repair.

In some embodiments, the second putty can additionally include aneffective amount of one or more additional therapeutic additives. By wayof non-limiting example, the one or more additional therapeuticadditives may be selected from the group consisting of antimicrobialagents, analgesics, anesthetics, antineoplastic agents,anti-inflammatories, radiopaque agents, biocompatible colorants,osteopromotive agents, growth factors, chemical-based hemostats (e.g.,thrombin, fibrin, oxidized cellulose, styptic agents, protamine,chitosan, cross-linked, purified plant starch (e.g., Arista), and/orcombinations thereof), and/or combinations thereof.

Also provided are compositions containing two putty components, thefirst putty (Putty A) including a mixture of potassium dihydrogenphosphate, magnesium oxide and at least one calcium-containing compound(e.g., tricalcium phosphate, hydroxyapatite, and/or combinationsthereof) all suspended in one or a mixture of anhydrous, non-toxic,partially water-miscible, inert suspension vehicles and the second putty(Putty B) including water, particles of previously unclotted mammalianblood plasma, and one or more viscosity-building agents (e.g., sodiumcarboxymethyl cellulose, sodium alginate, carrageenan, gelatin, collagenchitosan, and combinations thereof). In these compositions, whenthoroughly admixed, the first putty and the second putty can result inthe formation of a third putty (Putty C) that is a moldable, settablesurgical implant that is suitable for hard and soft tissue repair.

In some embodiments, the second putty can additionally include aneffective amount of one or more additional therapeutic additives. By wayof non-limiting example, the one or more additional therapeuticadditives may be selected from the group consisting of antimicrobialagents, analgesics, anesthetics, antineoplastic agents,anti-inflammatories, radiopaque agents, biocompatible colorants,osteopromotive agents, growth factors, chemical-based hemostats (e.g.,thrombin, fibrin, oxidized cellulose, styptic agents, protamine,chitosan, cross-linked, purified plant starch (e.g., Arista), and/orcombinations thereof), and/or combinations thereof.

In embodiments, the compositions described herein are particularlysuitable for use in bone repair, as bone void fillers, bone cements,and/or bone hemostats. In other embodiments, the compositions aresuitable for soft tissue repair, for example as soft tissue adhesives.

In embodiments, the compositions are provided in the form of a curableor settable composition, the composition being optionally sterile.

In embodiments, the composition is a putty-like composition comprising30-50% (i.e., 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43,44, 45, 46, 47, 48, 49, or 50% or 30-35, 30-40, 30-45, 35-40, 35-45,35-50, 40-45, 40-50, or 45-50%) and preferably 40% of calcium stearate,1-10% (i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10% or 1-2, 1-3, 1-4, 1-5,1-6, 1-7, 1-8, 1-9, 2-3, 2-4, 2-5, 2-6, 2-7, 2-8, 2-9, 2-10, 3-4, 3-5,3-6, 3-7, 3-8, 3-9, 3-10, 4-5, 4-6, 4-7, 4-8, 4-9, 4-10, 5-6, 5-7, 5-8,5-9, 5-10, 6-7, 6-8, 6-9, 6-10, 7-8, 7-9, 7-10, 8-9, 8-10, or 9-10%) andpreferably 5% of tocopheryl acetate, 20-40% (i.e., 20, 21, 22, 23, 24,25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40% or20-25, 20-30, 20-35, 25-30, 25-35, 25-40, 30-35, 30-40, or 35-40%) andpreferably 30% of Pluronic L-35 (i.e., a nonionic triblock copolymercomposed of a central hydrophobic chain of polyoxypropylene flanked bytwo hydrophilic chains of polyoxyethylene in liquid form, wherein themolecular weight of the hydrophobe is approximately 900 g/mol and anpolyethylene content of approximately 50%), 10-30% (i.e., 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or30% or 10-15, 10-20, 10-25, 15-20, 15-25, 15-30, 20-25, 20-30, or25-30%) and preferably 20% of ground and sieved human plasmalyophilizate and 1-8% (i.e., 1, 2, 3, 4, 5, 6, 7, or 8% or 1-2, 1-3,1-4, 1-5, 1-6, 1-7, 1-8, 2-3, 2-4, 2-5, 2-6, 2-7, 2-8, 3-4, 3-5, 3-6,3-7, 3-8, 4-5, 4-6, 4-7, 4-8, 5-6, 5-7, 5-8, 6-7, 6-8 or 7-8%) andpreferably 5% of an antimicrobial agent, e.g, tobramycin or gentamycin.In embodiments, this composition provides instant (within 0-5 (i.e., 0,1, 2, 3, 4, or 5) seconds) hemostasis when applied to bleeding bone, isbody absorbable within 30 days of implantation, and maintains zones ofinhibition against MRSA (Methicillin-resistant Staphylococcus aureus)for at least 4 days. In one embodiment, the calcium stearate iscompletely replaced by unclotted lyophilized human blood plasma.

In embodiments, the composition is a putty-like composition comprising45-65% (i.e., 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58,59, 60, 61, 62, 63, 64, or 65% or 45-50, 45-55, 45-60, 50-55, 50-60,50-65, 55-60, 55-65, or 60-65%) and preferably 54% of PEG stearate,1-10% (i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10% or 1-2, 1-3, 1-4, 1-5,1-6, 1-7, 1-8, 1-9, 2-3, 2-4, 2-5, 2-6, 2-7, 2-8, 2-9, 2-10, 3-4, 3-5,3-6, 3-7, 3-8, 3-9, 3-10, 4-5, 4-6, 4-7, 4-8, 4-9, 4-10, 5-6, 5-7, 5-8,5-9, 5-10, 6-7, 6-8, 6-9, 6-10, 7-8, 7-9, 7-10, 8-9, 8-10 or 9-10%) andpreferably 5% tocopheryl acetate, 3-10% (i.e., 3, 4, 5, 6, 7, 8, 9, or10% or 3-4, 3-5, 3-6, 3-7, 3-8, 3-9, 4-5, 4-6, 4-7, 4-8, 4-9, 4-10, 5-6,5-7, 5-8, 5-9, 5-10, 6-7, 6-8, 6-9, 6-10, 7-8, 7-9, 7-10, 8-9, 8-10 or9-10%) and preferably 6% of sodium carboxymethylcellulose, 5-15% (i.e.,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15% or 5-10 or 10-15%) andpreferably 10% of propylene oxide, 5-15% (i.e., 5, 6, 7, 8, 9, 10, 11,12, 13, 14, or 15% or 5-10 or 10-15%) and preferably 10% of PluronicL-121 (i.e., a nonionic triblock copolymer composed of a centralhydrophobic chain of polyoxypropylene flanked by two hydrophilic chainsof polyoxyethylene in liquid form, wherein the molecular weight of thehydrophobe is approximately 3,600 g/mol and an polyethylene content ofapproximately 10%) and 10-20% (i.e., 10, 11, 12, 13, 14, 15, 16, 17, 18,19, or 20% or 10-15 or 15-20%) and preferably 15% of milled and sievedhuman plasma lyophilizate. In embodiments, this composition providesinstant (within 0-5 (i.e., 0, 1, 2, 3, 4, or 5) seconds) hemostasis whenapplied to bleeding bone, is body absorbable within 8 days ofimplantation.

In embodiments, the composition is a putty-like composition comprising20-50% (i.e., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33,34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50%or 20-25, 20-30, 20-35, 20-40, 20-45, 25-30, 25-35, 25-40, 25-45, 25-50,30-35, 30-40, 30-45, 30-50, 35-40, 35-45, 35-50, 40-45, 40-50, or45-50%) and preferably 35% of phosphate-based ceramic, 20-40% (i.e., 20,21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38,39, or 40% or 20-25, 20-30, 20-35, 25-30, 25-35, 25-40, 30-35, 30-40, or35-40%) and preferably 30% of PEG stearate, 1-8% (i.e., 1, 2, 3, 4, 5,6, 7, or 8% or 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 2-3, 2-4, 2-5, 2-6,2-7, 2-8, 3-4, 3-5, 3-6, 3-7, 3-8, 4-5, 4-6, 4-7, 4-8, 5-6, 5-7, 5-8,6-7, 6-8 or 7-8%) and preferably 5% of sodium carboxymethyl cellulose,1-10% (i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10% or 1-2, 1-3, 1-4, 1-5,1-6, 1-7, 1-8, 1-9, 2-3, 2-4, 2-5, 2-6, 2-7, 2-8, 2-9, 2-10, 2-4, 3-5,3-6, 3-7, 3-8, 3-9, 4-5, 4-6, 4-7, 4-8, 4-9, 4-10, 5-6, 5-7, 5-8, 5-9,5-10, 6-7, 6-8, 6-9, 6-10, 7-8, 7-9, 7-10, 8-9, 8-10 or 9-10%) andpreferably 5% of tocopheryl acetate, 1-9% (i.e., 1, 2, 3, 4, 5, 6, 7, 8,or 9% or 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 2-3, 2-4, 2-5, 2-6, 2-7,2-8, 2-9, 3-4, 3-5, 3-6, 3-7, 3-8, 3-9, 4-5, 4-6, 4-7, 4-8, 4-9, 5-6,5-7, 5-8, 5-9, 6-7, 6-8, 6-9, 7-8, 7-9 or 8-9%)) and preferably 5% ofPluronic L-121 (i.e., a nonionic triblock copolymer composed of acentral hydrophobic chain of polyoxypropylene flanked by two hydrophilicchains of polyoxyethylene in liquid form, wherein the molecular weightof the hydrophobe is approximately 3,600 g/mol and an polyethylenecontent of approximately 10%) and 8-35% (i.e., 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32,33, 34, or 35% or 8-10, 8-15, 8-20, 8-25, 8-30, 10-15, 10-20, 10-25,10-30, 10-35, 15-20, 15-25, 15-30, 15-35, 20-25, 20-30, 20-35, 25-30,25-35, or 30-35%) and preferably 20% of milled and sieved human plasmalyophilizate. In embodiments, this composition provides instant (within0-5 (i.e., 0, 1, 2, 3, 4, or 5) seconds) hemostasis when applied tobleeding bone and reorganizes into new bone as it is resorbed.

In embodiments, the composition is a putty-like composition comprising aresorbable polymer derived from 10-20% (i.e., 10, 11, 12, 13, 14, 15,16, 17, 18, 19, or 20% or 10-15 or 15-20%) and preferably 15% oflactyldiester (i.e., esters of lactic acid) and 10-20% (i.e., 10, 11,12, 13, 14, 15, 16, 17, 18, 19, or 20% or 10-15 or 15-20%) andpreferably 15% of a polyesterpolyol,(i.e., esters of any polyol) 40-70%(i.e., 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55,56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or 70% or 40-45,40-50, 40-55, 40-60, 40-65, 45-50, 45-55, 45-60, 45-65, 45-70, 50-55,50-60, 50-65, 50-70, 55-60, 55-65, 55-70, 60-65, 60-70, or 65-70%) andpreferably 55% of powdered calcium phosphate, 1-10% (i.e., 1, 2, 3, 4,5, 6, 7, 8, 9, or 10% or 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 2-3,2-4, 2-5, 2-6, 2-7, 2-8, 2-9, 20-10, 3-4, 3-5, 3-6, 3-7, 3-8, 3-9, 4-5,4-6, 4-7, 4-8, 4-9, 4-10, 5-6, 5-7, 5-8, 5-9, 5-10, 6-7, 6-8, 6-9, 6-10,7-8, 7-9, 7-10, 8-9, 8-10, or 9-10%) and preferably 5% of tocopherylacetate, 1-10% (i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10% or 1-2, 1-3,1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 2-3, 2-4, 2-5, 2-6, 2-7, 2-8, 2-9, 20-10,3-4,3-5, 3-6, 3-7, 3-8, 3-9, 4-6, 4-7, 4-8, 4-9, 4-10, 5-7, 5-8, 5-9,5-10, 6-8, 6-9, 6-10, 7-9, 7-10, 8-10 or 9-10%) and preferably 5% ofglyceryl triester. Immediately after mixing these components into aputty, 10-20% (i.e., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20% or10-15 or 15-20%) and preferably 15% of milled and sieved human plasmalyophilizate is mixed into the putty. In embodiments, this compositionprovides instant (within 0-5 (0, 1, 2, 3, 4, or 5) seconds) hemostasiswhen applied to bleeding bone and is sufficiently adhesive 6 hours afterapplication to prevent postoperative micromotion in a wire-supportedreconstructed sheep sternotomy.

In embodiments, the compositions are provided in the form of a curableor settable composition comprising a plurality of component partspackaged separately, each of the component parts being sterile, andadapted to be mixed at time of use, where upon mixing a curing reactionis initiated. Additives such as lyophilized blood plasma may be added atthis time. Preferably, the component parts, once mixed, do not require acatalyst for curing.

In embodiments, the composition comprises four separately packagedcomponents that are combined and thoroughly mixed just prior to use. Thefirst component is 25-35% (i.e., 25, 26, 27, 28, 29, 30, 31, 32, 33, 34,or 35% or 25-30 or 30-35%), preferably 30% of the composition andcomprises a liquid prepolymer containingmethylene-bis-diphenyldiisocyanate. The second component is 25-35%(i.e., 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35% or 25-35 or30-35%), preferably 30% of the composition and comprises a liquid Castoroil-based polyol. The third component is 20-30% (i.e., 20, 21, 22, 23,24, 25, 26, 27, 28, 29, or 30% or 25-30 or 30-35%), preferably 25% ofthe composition and comprises powdered calcium carbonate and the fourthcomponent, added after the first three components have been mixed andtransformed into a settable taffy-like phase, is 10-20% (i.e., 10, 11,12, 13, 14, 15, 16, 17, 18, 19, or 20% or 10-15 or 15-20%), preferably15% of the composition and comprises ground and sieved human plasmalyophilizate. In embodiments, this composition provides instant (within0-5 (i.e., 0, 1, 2, 3, 4, or 5) seconds) hemostasis when applied tobleeding bone and is sufficiently adhesive after 12 hours to securelyadhere two non-weight bearing bone surfaces together.

The terms “settable” and “curable” and the like are used interchangeablyherein. In one embodiment, the fully cured composition has mechanicalproperties suitable for drilling and/or accepting a surgical screwwithout shattering or splintering. In one embodiment, the componentparts of the composition are in the form of a putty or paste which ismoldable, preferably hand-moldable, and in some embodiments sufficientlyflowable for extrusion, for example, from a syringe. The homogenouscomposition formed from the mixture of the component parts is also inthe form of a putty or paste which is moldable, preferablyhand-moldable, and in some embodiments sufficiently flowable forextrusion, for a period of time after mixing and during curing. In oneembodiment, the period of time for complete cure into a hardened finalform is from about 6 to 12 (i.e., 6, 7, 8, 9, 10, 11, or 12) hours orfrom about 6 to 24 (i.e., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19, 20, 21, 22, 23, or 24) hours. In one embodiment, the fully curedcomposition is drillable or machineable. In one embodiment, the settablecomposition cures into a final form that is thermoplastic and can besoftened to return it to a hand-moldable state by applying heatsufficient to warm the composition to a temperature at least higher than40° C., preferably between 40° C. and 100° C. (i.e., 40, 41, 42, 43, 44,45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62,63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80,81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98,99, or 100° C.). In accordance with this embodiment, where thecomposition sets or cures prematurely during use, it may be heated untilit becomes moldable again for a period of time until it cools. Thecompositions described herein and their component parts are preferablynot in a low viscosity liquid form.

In one embodiment, the component parts may each comprise an additive,such as a colorant or dye, that imparts a color to the component. In oneembodiment, each component comprises a different colorant or dye suchthat when the component parts are combined to form the settablecomposition, the different colors mix to form a new color, which newcolor is also indicative that the composition has been mixed tohomogeneity. In one embodiment, the component parts can be mixed tohomogeneity within about 1 minute or less, or within about 2 minutes.

The disclosure also provides related compositions, including surgicalkits and packages, as well as methods of making and using any of thesettable compositions described herein. In one embodiment, thedisclosure provides a package comprising one or a plurality of settablecompositions, each composition consisting of a set of two or moreindividual components, the components of a set comprising amounts ofreagents which, upon mixing, react and cure into a final hardened formover a period of time, preferably at room or body temperature. Eachcomponent is physically separated from the other components of the setwithin the package, and optionally, from other sets of components. Inone embodiment, the set consists of 2, 3, or 4 individual components. Inone embodiment, the components are sterile. In one embodiment, thepackage is adapted to permit the removal of one set of components at atime while leaving the remaining sets in a sealed, sterile, environment.In one embodiment, the package comprises an upper peelable filmconfigured to allow the exposure of one set of putties at a time. In oneembodiment, each component is physically separated from the othercomponents of its set within the package by means of a compartment orplurality of compartments in the package. In a further embodiment, eachset of components may optionally be separated from other sets of thepackage by perforations allowing the set to be conveniently separatedeither before or after opening and removing the contents.

In one embodiment, the plurality of compartments comprises depressionsor wells in a heat-sealable metal foil-based sheet. In one embodiment,the compartments of a set are flexible and separated by at least onebreakable seal adapted to allow the component putties of the set to bemixed together when the seal is broken. In one embodiment, thecompartments are in the form of one or more syringes, preferably one ormore foil-enclosed syringes. In one embodiment, the compartments are inthe form of a single syringe, preferably a foil-enclosed syringe,adapted to maintain individual component putties of a set separated fromeach other within the single syringe. In one embodiment, thecompartments are in the form of a plurality of syringes and each syringecontains a single component of a set. In one embodiment, eachcompartment comprises one or more surfaces in contact with an individualcomponent, the one or more surfaces comprising or consisting of a lowsurface energy material selected, for example, from the group consistingof polytetrafluoroethylene (PTFE), silicone, polypropylene,polyethylene, and polystyrene.

In one embodiment, the package further comprises an outer, heatsealable, preferably water impermeable or water resistant envelopecompletely surrounding the package, and a desiccant. In one embodiment,the outer envelope is a heat sealed, water impermeable or waterresistant foil package.

Provided herein are bone hemostatic and adhesive composition comprisinga first component (also referred to as component A) and a secondcomponent (also referred to as component B), wherein the first componentcomprises a polyfunctional isocyanate compound, one or more polyols, anda particulate component, wherein the second putty comprises apolyfunctional isocyanate compound one or more polyols or one or moreamines or both and a particulate component, wherein the particulatecomponent comprises one or more particulate materials, and wherein thefirst and the second components are mixed together to form abioabsorbable, homogenous putty.

In some embodiments, the first component comprises 30% to 40% of apolyfunctional isocyanate compound, 0% to 3% of one or more polyols, and50-65% of a particulate component, based upon the total weight of thefirst putty, the second putty comprises 3% to 5% of a polyfunctionalisocyanate compound, 0.5 to 15% of one or more polyols, and 70% to 85%of a particulate component, based upon the total weight of the secondputty, wherein the particulate component comprises one or moreparticulate materials, and wherein the first and the second putties aremixed together to form a bioabsorbable, homogenous putty.

In some embodiments, the first component comprises less than 0.5% of oneor more polyols, based upon the total weight of the first putty, and thesecond putty comprises 0.5 to 15% of one or more polyols, based upon thetotal weight of the second putty. In a preferred embodiment, the firstcomponent comprises 0% of one or more polyols, based upon the totalweight of the first putty.

In some embodiments, the first component comprises 30% to 40% of apolyfunctional isocyanate compound, less than 0.5% of one or morepolyols, and 50-65% of a particulate component, based upon the totalweight of the first putty, the second putty comprises 3% to 5% of apolyfunctional isocyanate compound, 0.5 to 15% of one or more polyols,and 70% to 85% of a particulate component, based upon the total weightof the second putty, wherein the particulate component comprises one ormore particulate materials, and wherein the first and the second puttiesare mixed together to form a bioabsorbable, homogenous putty.

In some embodiments, the first component comprises 30% to 35% of apolyfunctional isocyanate compound, based upon the total weight of thefirst component, and the second component comprises 3% to 5% of apolyfunctional isocyanate compound, based upon the total weight of thesecond component. In some embodiments, the first component comprises 35%to 40% of a polyfunctional isocyanate compound, based upon the totalweight of the first component, and the second component comprises 3% to5% of a polyfunctional isocyanate compound, based upon the total weightof the second component.

In some embodiments, the first component comprises 2% to 3% of one ormore polyols, based upon the total weight of the first component, andthe second component comprises 0.5% to 5% of one or more polyols, basedupon the total weight of the second component. In some embodiments, thefirst component comprises 2% to 3% of one or more polyols, based uponthe total weight of the first component, and the second componentcomprises 1.5% to 5% of one or more polyols, based upon the total weightof the second component. In some embodiments, the first componentcomprises 0% to 2% of one or more polyols, based upon the total weightof the first component, and the second component comprises 2% to 10% ofone or more polyols, based upon the total weight of the secondcomponent. In some embodiments, the first component comprises 0% to 2%of one or more polyols, based upon the total weight of the firstcomponent, and wherein the second component comprises 10% to 15% of oneor more polyols, based upon the total weight of the second component.

In some embodiments, the first component comprises 60% to 65% of aparticulate component, based upon the total weight of the firstcomponent, and the second component comprises 80% to 85% of aparticulate component, based upon the total weight of the second putty.In some embodiments, the first component comprises 55% to 60% of aparticulate component, based upon the total weight of the firstcomponent, and the second component comprises 80% to 85% of aparticulate component, based upon the total weight of the secondcomponent. In some embodiments, the first component comprises 50% to 55%of a particulate component, based upon the total weight of the firstcomponent, and the second component comprises 70% to 75% of aparticulate component, based upon the total weight of the secondcomponent.

In some embodiments, the homogenous component comprises about 0.1% toabout 5% of one or more additives, based upon the total weight of thehomogenous component. In some embodiments, the homogenous componentcomprises about 0.9% to about 5% of one or more additives, based uponthe total weight of the homogenous component. In some embodiments, thehomogenous component comprises about 1% to about 5% of one or moreadditives, based upon the total weight of the homogenous component.

In some embodiments, the polyfunctional isocyanate compound is aromaticisocyanate, an aliphatic isocyanate, a cycloaliphatic isocyanate, and anadduct of an isocyanate. In some embodiments, the polyfunctionalisocyanate compound is any one of an absorbable lactide diester (ALD),ethyl lysine diisocyanate, cyclohexyl diisocyanate, hexamethylenediisocyanate, a hexamethylene diisocyanate trimer, a hexamethylenediisocyanate biuret, a methylene bis-diphenyldiisocyanate, a lysinediisocyanate, a diphenylmethanediisocyanate (MDI),4,4-diphenylmethanediisocyanate, a mixture of2,4′-diphenylmethanediisocyanate and 4,4′-diphenylmethanediisocyanateisomers, a polycarbodiimide-modified diphenylmethane disocyanate,polymethylene polyphenylisocyanate. In a preferred embodiment, thepolyfunctional isocyanate compound is an absorbable lactide diester(ALD).

In some embodiments, the one or more polyols is any one of ethyleneglycol, diethylene glycol, propanediol, 1,2-propanediol (propyleneglycol), 1,3-propanediol, 1,2-ethanediol (ethylene glycol), butanediol,1,4-butanediol, 1,5-pentanediol, 1,3-cyclopentanediol, 1,6-hexanediol,1,8-octanediol, polytetramethylene ether glycols, polyols derived fromglycolide, lactide, trimethylenecarbonate, p-dioxanone, polycaprolactonepolyol, polycaprolactone triol polyester polyol, polyadipate polyol,diol, poly(butane-adipate) diol, poly(ethylene/propylene-adipate) diol,poly(hexane/adipate/isophthalate diol)), poly(oxypropylene) glycol,apoly(oxytetramethylene) glycol, and poly(oxyethylene) glycols,polycaprolactone co-glycolide, a polycaprolactone co-lactide ortriethanolamine (TEOA) or a combination thereof. In a preferredembodiment, the one or more polyols is a polycaprolactone triol, abutanediol, a triethanolamine or a combination thereof.

In some embodiments, the particulate matter is any one of calciumphosphate, siliconized calcium phosphate, substituted calciumphosphates, calcium pyrophosphate, calcium stearate, barium sulfate, acalcium, magnesium, zinc, aluminum or barium salt of lauric acid, acalcium, magnesium, zinc, aluminum or barium salt of myristic acid; acalcium, magnesium, zinc, aluminum or barium salt of palmitic acid, acalcium, magnesium, zinc, aluminum and/or barium salt of stearic acid, acalcium, magnesium, zinc, aluminum or barium salt of arachidic acid, acalcium, magnesium, zinc, aluminum or barium salt of behenic acid,polyethylene glycol (PEG) laurate, PEG stearate, PEG palmitate, PEGbehenate, hydroxyapatite, polymethyl methacrylate, glass-ionomer,absorbable phosphate glass, calcium sulfate, tricalcium phosphate,calcium carbonate, magnesium carbonate, aluminum carbonate, ironcarbonate, zinc carbonate, calcium bicarbonate, sodium bicarbonate,demineralized bone, or mineralized bone or a combination thereof. In apreferred embodiment, the particulate matter is calcium phosphate,calcium stearate or a combination thereof.

In some embodiments, the particulate component of the first componentcomprises 0% to 1% of calcium stearate, and 53% to 62% of calciumphosphate, based upon the total weight of the first component, and theparticulate component of the second component comprises about 0.1 toabout 0.5% of calcium stearate, and 70% to 84% of calcium phosphate,based upon the total weight of the second component.

In some embodiments, the homogenous composition formed by mixing thefirst and the second component, comprises 0.2% to 1% of calciumstearate, and 56% to 73% of calcium phosphate, based upon the totalweight of the homogenous composition.

In some embodiments, the particulate material of the first componentcomprises a combination of barium sulfate, calcium stearate, calciumphosphate or a combination thereof. In some embodiments, the firstcomponent comprises 1% to 10% of barium sulfate, 1% to 2% of calciumstearate and 48% to 53% of calcium phosphate, based upon the totalweight of the first component, and the second component comprises 0.1%to 0.5% of calcium stearate and 70% to 75% of calcium phosphate, basedupon the total weight of the second component.

In some embodiments, the homogenous composition formed by mixing thefirst and the second component, comprises 0.5% to 8.5% of bariumsulfate, 0.2% to 1% of calcium stearate and 50% to 65% of calciumphosphate based on the weight of the homogenous composition.

In some embodiment, the one or more additives is any one of anantioxidant, a colorant, a steroid, calcium stearate, tocopherylacetate, or triacetin or a combination thereof. In a preferredembodiment, the one or more additives comprises tocopheryl acetate, ortriacetin or a combination thereof.

In some embodiments, the first component comprises 0% of triacetin,based upon the total weight of the first component, and the secondcomponent comprises about 0.5% to about 2% of triacetin, based upon thetotal weight of the second component. In some embodiments, thehomogenous composition formed by mixing the first and the secondcomponent, comprises about 0.1% to about 1% triacetin, based upon thetotal weight of the homogenous composition.

In some embodiments, the first component comprises about 6% to about 7%of tocopheryl acetate, based upon the total weight of the firstcomponent, and the second component comprises about 0% to about 4% oftocopheryl acetate, based upon the total weight of the second component.In some embodiments, the homogenous composition formed by mixing thefirst and the second component, comprises about 5% to about 6% oftocopheryl acetate, based upon the total weight of the homogenouscomposition.

In some embodiments, the homogenous composition formed by mixing thefirst and the second components, comprises 20% to 40% of a polyurethanecopolymer, based upon the total weight of the homogenous composition.

In some embodiments, the homogenous composition formed by mixing thefirst and the second components, comprises a polyurethane co-polymercomprising of an Absorbable Lactide Diester-PolycaprolactoneTriol-Butanediol (ALD-PCL-BDO) polymer. In some embodiments, thehomogenous composition comprises a polyurethane co-polymer comprising ofan Absorbable Lactide Diester (ALD)-Polycaprolactone Triol(PCL)-Butanediol (BDO)-Triethanolamine (TEOA) polymer (ALD-PCL-BDO-TEOApolymer).

In some embodiments, the first component, the second component and thehomogenous composition formed by mixing the first and the secondcomponents are a putty. In some embodiments, the homogenous compositionformed by mixing the first and the second components is moldable orhand-settable.

In some embodiments, the first component, the second component and thehomogenous composition formed by mixing the first and the secondcomponents are a paste. In some embodiments, the homogenous compositionformed by mixing the first and the second components is a flowablepaste.

In one embodiment, the settable composition consists of a set ofcomponents, each in the form of a putty, that, upon mixing, react andcure into a polyurethane or polyureaurethane composition. In oneembodiment, at least one or at least two of the putty components of theset comprises an isocyanate component, a polyol/polyamine component, anda particulate component (for example, the first putty may comprise apolyfunctional isocyanate, tocopheryl acetate, calcium phosphateparticles and a polyol and the second putty may comprise apolyfunctional isocyanate, calcium phosphate particles, at least onepolyol, a fatty acid salt and tocopherol acetate). In one embodiment,the particulate component is present in an amount of about 5-85 wt %(i.e., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39,40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57,58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75,76, 77, 78, 79, 80, 81, 82, 83, 84, or 85 wt % or 5-10, 5-15, 5-20,5-25, 5-30, 5-35, 5-40, 5-45, 5-50, 5-55, 5-60, 5-65, 5-70, 5-75, 5-80,10-15, 10-20, 10-25, 10-30, 10-35, 10-40, 10-45, 10-50, 10-55, 10-60,10-65, 10-70, 10-75, 10-80, 10-85, 15-20, 15-25, 15-30, 15-35, 15-40,15-45, 15-50, 15-55, 15-60, 15-65, 15-70, 15-75, 15-80, 15-85, 20-25,20-30, 20-35, 20-40, 20-45, 20-50, 20-55, 20-60, 20-65, 20-70, 20-75,20-80, 20-85, 25-30, 25-35, 25-40, 25-45, 25-50, 25-55, 25-60, 25-65,25-70, 25-75, 25-80, 25-85, 30-35, 30-40, 30-45, 30-50, 30-55, 30-60,30-65, 30-70, 30-75, 30-80, 30-85, 35-40, 35-45, 35-50, 35-55, 35-60,35-65, 35-70, 35-75, 35-80, 35-85, 40-45, 40-50, 40-55, 40-60, 40-65,40-70, 40-75, 40-80, 40-85, 45-50, 45-55, 45-60, 45-65, 45-70, 45-75,45-80, 45-85, 50-55, 50-60, 50-65, 50-70, 50-75, 50-80, 50-85, 55-60,55-65, 55-70, 55-75, 55-80, 55-85, 60-65, 60-70, 60-75, 60-75, 60-80,60-85, 65-70, 65-75, 65-80, 65-85, 70-75, 70-80, 70-85, 75-80, 75-85, or80-85 wt%) based on the weight of the putty component. In oneembodiment, the particulate component is selected from one or more ofcalcium sulfate, calcium phosphosilicate, sodium phosphate, calciumaluminate, calcium phosphate, magnesium phosphate, hydroxyapatite,phosphate glass, biomimetic carbonate apatite, biphasic calciumphosphate/hydroxyapatite, demineralized bone matrix, mineralized bone,lyophilized human blood plasma, or non-resorbable metallic or polymericmaterials, such as polytetrafluoroethylene, polymethylmethacrylate,micronized titanium and powdered stainless steel. The particulatecomponent may comprise two or more different particulates.

In one embodiment, the set consists of two putties, A and B, and theisocyanate component consists of a diisocyanate which is aromatic oraliphatic. Putty A comprises 15-40% (i.e., 15, 16, 17, 18, 19, 20, 21,22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39,or 40% or 15-20, 15-25, 15-30, 15-35, 20-25, 20-30, 20-35, 20-40, 25-30,25-35, 25-40, 30-35, 30-40, or 35-40%) of the isocyanate component,0.5-5% (i.e., 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6,1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1,3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4., 4.5,4.6, 4.7, 4.8, 4.9, or 5% or 0.5-1, 0.5-1.5, 0.5-2, 0.5-2.5, 0.5-3.0,0.5-3.5, 0.5-4.0, 0.5-4.5,1-1.5, 1-2, 1-2.5, 1-3, 1-3.5, 1-4, 1-4.5,1-5, 1.5-2, 1.5-2.5, 1.5-3, 1.5-3.5, 1.5-4, 1.5-4.5, 1.5-5, 2-2.5, 2-3,2-3.5, 2-4, 2-4.5, 2-5, 2.5-3, 2.5-3.5, 2.5-4, 2.5-4.5, 2.5-5, 3-3.5,3-4, 3-4.5, 3-5, 3.5-4, 3.5-4.5, 3.5-5, 4-4.5, 4-5, or 4.5-5%) of thepolyol component, and 50-75% (i.e., 50, 51, 52, 53, 54, 55, 56, 57, 58,59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, or 75%or 50-55, 50-60, 50-65, 50-70, 55-60, 55-65, 55-70, 55-75, 60-65, 60-70,60-75, 65-70, 65-75, or 70-75%) particulate material, based upon totalweight of Putty A; Putty B comprises 1-10% (i.e., 1, 2, 3, 4, 5, 6, 7,8, 9, or 10% or 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 2-3, 2-4, 2-5,2-6, 2-7, 2-8, 2-9, 2-10, 3-4, 3-5, 3-6, 3-7, 3-8, 3-9, 4-5, 4-6, 4-7,4-8, 4-9, 4-10, 5-6, 5-7, 5-8, 5-9, 5-10, 6-7, 6-8, 6-9, 6-10, 7-8, 7-9,7-10, 8-9, 8-10 or 9-10) of the isocyanate component, 3-15% (i.e., 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15% or 3-5, 3-10, 5-10, 5-15, or10-15%) of the polyol component, and 65-95% (i.e., 65, 66, 67, 68, 69,70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87,88, 89, 90, 91, 92, 93, 94, or 95% or 65-70, 65-75, 65-80, 65-90, 70-75,70-80, 70-85, 70-90, 70-95, 75-80, 75-85, 75-90, 75-95, 80-85, 80-90,80-95, 85-90, 85-95, or 90-95%) or 75-85% (i.e., 75, 76, 77, 78, 79, 80,81, 82, 83, 84, or 85% or 75-80 or 80-85) particulate material, basedupon total weight of Putty B. In one embodiment, the polyol in Putty Ais present in a prepolymer with the isocyanate component such that thereis substantially no unreacted polyol in Putty A and the isocyanatecomponent in Putty B is present in a prepolymer such that there issubstantially no unreacted isocyanate in Putty B.

In one embodiment, the set consists of two putties, A and B. Putty Acomprises 15-40% (i.e., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26,27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40% or 15-20,15-25, 15-30, 15-35, 20-25, 20-30, 20-35, 20-40, 25-30, 25-35, 25-40,30-35, 30-40, or 35-40%) of the isocyanate component, 0.5-5% (i.e., 0.5,0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2,2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5,3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4., 4.5, 4.6, 4.7, 4.8, 4.9, or5% or 0.5-1, 0.5-1.5, 0.5-2, 0.5-2.5, 0.5-3.0, 0.5-3.5, 0.5-4.0,0.5-4.5,1-1.5, 1-2, 1-2.5, 1-3, 1-3.5, 1-4, 1-4.5, 1-5, 1.5-2, 1.5-2.5,1.5-3, 1.5-3.5, 1.5-4, 1.5-4.5, 1.5-5, 2-2.5, 2-3, 2-3.5, 2-4, 2-4.5,2-5, 2.5-3, 2.5-3.5, 2.5-4, 2.5-4.5, 2.5-5, 3-3.5, 3-4, 3-4.5, 3-5,3.5-4, 3.5-4.5, 3.5-5, 4-4.5, 4-5, or 4.5-5%) of the polyol component,and 40-85% (i.e., 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52,53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70,71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, or 85% or 40-45,40-50, 40-55, 40-60, 40-65, 40-70, 40-75, 40-80, 45-50, 45-55, 45-60,45-65, 45-70, 45-75, 45-80, 45-85, 50-55, 50-60, 50-65, 50-70, 50-75,50-80, 50-85, 55-60, 55-65, 55-70, 55-75,55-80, 55-85, 60-65, 60-70,60-75, 60-80, 60-85, 65-70, 65-75, 65-70, 65-75, 65-80, 65-85, 70-75,70-80, 70-85, 75-80, 75-85, or 80-85%) particulate material, based upontotal weight of Putty A; Putty B comprises 1-10% (i.e., 1, 2, 3, 4, 5,6, 7, 8, 9, or 10% or 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 2-3, 2-4,2-5, 2-6, 2-7, 2-8, 2-9, 2-10, 3-4, 3-5, 3-6, 3-7, 3-8, 3-9, 4-5, 4-6,4-7, 4-8, 4-9, 4-10, 5-6, 5-7, 5-8, 5-9, 5-10, 6-7, 6-8, 6-9, 6-10, 7-8,7-9, 7-10, 8-9, 8-10 or 9-10) of the isocyanate component, 3-15% (i.e.,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15% or 3-5, 3-10, 5-10,5-15, or 10-15%) of the polyol component, and 65-95% (i.e., 65, 66, 67,68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85,86, 87, 88, 89, 90, 91, 92, 93, 94, or 95%) or 75-85% (i.e., 75, 76, 77,78, 79, 80, 81, 82, 83, 84, or 85% or 65-70, 65-75, 65-80, 65-90, 70-75,70-80, 70-85, 70-90, 70-95, 75-80, 75-85, 75-90, 75-95, 80-85, 80-90,80-95, 85-90, 85-95, or 90-95%) particulate material, based upon totalweight of Putty B. [67] In one embodiment, the set consists of twopastes, A and B. Paste A comprises 15-40% (i.e., 15, 16, 17, 18, 19, 20,21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38,39, or 40% or 15-20, 15-25, 15-30, 15-35, 20-25, 20-30, 20-35, 20-40,25-30, 25-35, 25-40, 30-35, 30-40, or 35-40%) of the isocyanatecomponent, 0.5-5% (i.e., 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4,1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9,3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4.,4.5, 4.6, 4.7, 4.8, 4.9, or 5% or 0.5-1, 0.5-1.5, 0.5-2, 0.5-2.5,0.5-3.0, 0.5-3.5, 0.5-4.0, 0.5-4.5,1-1.5, 1-2, 1-2.5, 1-3, 1-3.5, 1-4,1-4.5, 1-5, 1.5-2, 1.5-2.5, 1.5-3, 1.5-3.5, 1.5-4, 1.5-4.5, 1.5-5,2-2.5, 2-3, 2-3.5, 2-4, 2-4.5, 2-5, 2.5-3, 2.5-3.5, 2.5-4, 2.5-4.5,2.5-5, 3-3.5, 3-4, 3-4.5, 3-5, 3.5-4, 3.5-4.5, 3.5-5, 4-4.5, 4-5, or4.5-5%) of the polyol component, and 50-75% (i.e., 50, 51, 52, 53, 54,55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72,73, 74, or 75%, 50-55, 50-60, 50-65, 50-70, 55-60, 55-65, 55-70, 55-75,60-65, 60-70, 60-75, 65-70, 65-75, or 70-75%) particulate material,based upon total weight of Paste A; Paste B comprises 1-10% (i.e., 1, 2,3, 4, 5, 6, 7, 8, 9, or 10 or 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9,2-3, 2-4, 2-5, 2-6, 2-7, 2-8, 2-9, 2-10, 3-4, 3-5, 3-6, 3-7, 3-8, 3-9,4-5, 4-6, 4-7, 4-8, 4-9, 4-10, 5-6, 5-7, 5-8, 5-9, 5-10, 6-7, 6-8, 6-9,6-10, 7-8, 7-9, 7-10, 8-9, 8-10 or 9-10%) of the isocyanate component,3-15% (i.e., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15% or 3-5,3-10, 5-10, 5-15, or 10-15%) of the polyol component, and 25-50% (i.e.,25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42,43, 44, 45, 46, 47, 48, 49, or 50% or 25-30, 25-35, 25-40, 25-45, 30-35,30-40, 30-45, 30-50, 35-40, 35-45, 35-50, 40-45, or 45-50%) or 5-25%(i.e., 5, 6, 7, 8, 9 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 24, or 25% or 5-10, 5-15, 5-20, 10-15, 10-20, 10-25, 15-20, 15-25,or 20-25%) particulate material, based upon total weight of Paste B.

In one embodiment, the set consists of two pastes, A and B. Paste Acomprises 15-40% (i.e., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26,27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40% or 15-20,15-25, 15-30, 15-35, 20-25, 20-30, 20-35, 20-40, 25-30, 25-35, 25-40,30-35, 30-40, or 35-40%) of the isocyanate component, 0.5-5% (i.e., 0.5,0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2,2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5,3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4., 4.5, 4.6, 4.7, 4.8, 4.9, or5% or 0.5-1, 0.5-1.5, 0.5-2, 0.5-2.5, 0.5-3.0, 0.5-3.5, 0.5-4.0,0.5-4.5,1-1.5, 1-2, 1-2.5, 1-3, 1-3.5, 1-4, 1-4.5, 1-5, 1.5-2, 1.5-2.5,1.5-3, 1.5-3.5, 1.5-4, 1.5-4.5, 1.5-5, 2-2.5, 2-3, 2-3.5, 2-4, 2-4.5,2-5, 2.5-3, 2.5-3.5, 2.5-4, 2.5-4.5, 2.5-5, 3-3.5, 3-4, 3-4.5, 3-5,3.5-4, 3.5-4.5, 3.5-5, 4-4.5, 4-5, or 4.5-5%) of the polyol component,and 40-85% (i.e., 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52,53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70,71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, or 85% or 40-45,40-50, 40-55, 40-60, 40-65, 40-70, 40-75, 40-80, 45-50, 45-55, 45-60,45-65, 45-70, 45-75, 45-80, 45-85, 50-55, 50-60, 50-65, 50-70, 50-75,50-80, 50-85, 55-60, 55-65, 55-70, 55-75,55-80, 55-85, 60-65, 60-70,60-75, 60-80, 60-85, 65-70, 65-75, 65-70, 65-75, 65-80, 65-85, 70-75,70-80, 70-85, 75-80, 75-85, or 80-85%) particulate material, based upontotal weight of Paste A; Paste B comprises 1-10% (i.e., 1, 2, 3, 4, 5,6, 7, 8, 9, or 10% or 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 2-3, 2-4,2-5, 2-6, 2-7, 2-8, 2-9, 2-10, 3-4, 3-5, 3-6, 3-7, 3-8, 3-9, 4-5, 4-6,4-7, 4-8, 4-9, 4-10, 5-6, 5-7, 5-8, 5-9, 5-10, 6-7, 6-8, 6-9, 6-10, 7-8,7-9, 7-10, 8-9, 8-10 or 9-10) of the isocyanate component, 3-15% (i.e.,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15% or 3-5, 3-10, 5-10,5-15, or 10-15%) of the polyol component, and 25-50% (i.e., 25, 26, 27,28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45,46, 47, 48, 49, or 50% or 25-30, 25-35, 25-40, 25-45, 30-35, 30-40,30-45, 30-50, 35-40, 35-45, 35-50, 40-45, or 45-50%) or 5-25% (i.e., 5,6, 7, 8, 9 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24,or 25% or 5-10, 5-15, 5-20, 10-15, 10-20, 10-25, 15-20, 15-25, or20-25%) particulate material, based upon total weight of Paste B.

In some embodiments, the composition provided herein has mechanicalproperties suitable for drilling and/or accepting a surgical screwwithout shattering or splintering. In some embodiment, the compositionprovided herein can be used in combination with a surgical hardware,e.g. a screw, a plate, a mesh, a wire, a rod or a nail, wherein thecomposition is used as an adhesive to keep the surgical hardware incontact with a bone. In one embodiment, the composition provided hereincan be used in combination with a surgical hardware, e.g. a screw, aplate, a mesh, a wire, a rod or a nail, wherein the composition is usedas a material to drill, affix or insert the surgical hardware. In someembodiments, the surgical hardware can be a cannulated surgicalhardware, wherein the cannulation of the surgical hardware comprises thecomposition disclosed herein. In some embodiments, the cannulatedsurgical hardware can comprise at least one fenestration to allow thecomposition to extrude from the cannulation of the surgical hardwareinto the surrounding bone.

Provided herein, is a cannulated bone screw having a shaft, a tip, and ahead, at least a portion of said shaft having threads thereon configuredto be inserted into a bone, wherein the screw comprises a cannulationalong the shaft comprising an amount of the homogenous compositiondisclosed herein within the cannulation, and at least one fenestrationdisposed along the shaft of the screw and connected to the cannulationof the screw, wherein the fenestration allows the composition to passthrough the at least one fenestration of the screw into a bone.

Provided herein is a method of delivering a bone hemostatic and adhesivecomposition into a site in a bone of a patient in need thereof, themethod comprising: a) providing the cannulated bone screw disclosedherein; b) inserting the cannulated bone screw into the bone of thepatient; and c) allowing the amount of the composition within the bonescrew to be delivered into the bone.

In some embodiment, the composition of the present disclosure can be foruse in a method of securing a surgical hardware into a bone of a subjectin need thereof, wherein the surgical hardware has a body and an openingat a point of the body, wherein the surgical hardware is cannulatedinside the body of the hardware, and comprises at least one fenestrationalong the body of the hardware for receiving the composition, whereinthe method comprises: a) inserting the surgical hardware into a site onthe bone; b) delivering the composition hardware inside through theopening into the cannulation in the body of the surgical hardware; c)allowing the composition to pass through the fenestration of thesurgical hardware into an area surrounding the hardware in the bone; andd) allowing the composition to harden to secure the surgical hardware tothe bone. In some embodiments, the surgical hardware can be a screw, aplate, a mesh, a wire, a rod or a nail or equivalent thereof.

Also provided are methods for closing a wound by applying a compositiondescribed herein to a wound in an amount sufficient to achieve woundclosure. In embodiments, methods are provided for achieving hemostasisat a wound site by applying a composition described herein to thebleeding wound in an amount sufficient to stop the flow of blood withina period of time, as described herein.

In one embodiment, provided herein are biocompatible settablecompositions consisting of a plurality of component parts which, uponmixing, react to form a cured final composition at room or bodytemperature over a period time, the final composition optionally beingbiodegradable under physiological conditions. In one embodiment, theplurality of component parts consists of two parts, A and B, part Acomprising a mixture of potassium dihydrogen phosphate, magnesium oxideand at least one calcium-containing compound all suspended in one or amixture of anhydrous, non-toxic, partially water-miscible, inertsuspension vehicles and part B comprising water, particles of previouslyunclotted mammalian blood plasma, and one or more viscosity-buildingagents. In one embodiment, the plurality of component parts consists oftwo parts, A and B, part A comprising potassium dihydrogen phosphate ordibasic sodium phosphate, or optionally magnesium oxide and a calciumcontaining compound suspended in one or a mixture of anhydrous partiallyor completely water miscible suspension vehicles and B comprises aviscosity building agent selected from one or more of a sodium, calciumor aluminum phyllosilicate or montmorillonite, a water absorbing clay, awater-absorbing polyacrylic acid, gelatin, sodium carboxymethylcellulose and hyprocellulose, and, optionally, a particulate materialselected from tricalcium phosphate, lyophilized human blood plasma,hydroxyapatite, or a mixture thereof. In one embodiment, the calciumcontaining compound is selected from tricalcium phosphate andhydroxyapatite, or a mixture thereof. In one embodiment, component Bfurther comprises one or more additives selected from a colorant, anantioxidant, a lyophilized human blood plasma and one or moretherapeutic agents. In one embodiment, the therapeutic agent is selectedfrom one or more of an anticancer agent, an antimicrobial agent, ananesthetic agent, an analgesic agent and/or an osteogenic agent. In oneembodiment, each component of a set of two contains a different colorantselected from primary or secondary hues such that when the coloredcomponents are mixed, the colors combine to form a third color which maybe used to visually indicate homogeneity of the mixture. In oneembodiment, the components can be hand mixed to homogeneity in oneminute, three minutes, nine minutes, or twelve minutes. In oneembodiment, one or more individual components contains analkylpyrrolidone. In one embodiment, the first component is derived froma putty-like, concentrated aqueous solution of an optionallycrosslinkable polyanionic polymer and the second component derived froma putty-like concentrated solution of an optionally crosslinkablepolycationic polymer. In one embodiment, about 0.1- 5% (i.e., 0.1, 0.2,0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7,1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2,3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4., 4.5, 4.6,4.7, 4.8, 4.9, or 5% or 0.1-1, 0.1-1.5, 0.1-2, 0.1-2.5, 0.1-3, 0.1-3.5,0.1-4, 0.1-4.5, 0.5-1, 0.5-1.5, 0.5-2, 0.5-2.5, 0.5-3, 0.5-3.5, 0.5-4,0.5-4.5, 0.5-5, 1-1.5, 1-2, 1-2.5, 1-3, 1-3.5, 1-4, 1-4.5, 1-5, 1.5-2,1.5-2.5, 1.5-3, 1.5-3.5, 1.5-4, 1.5-4.5, 1.5-5, 2-3, 2-3.5, 2-4, 2-4.5,2-5, 2.5-3, 2.5-3.5, 2.5-4, 2.5-4.5, 2.5-5, 3-3.5, 3-4, 3-4.5, 3-5,3.5-4, 3.5-4.5, 3.5-5, 4-4.5, 4-5, or 4.5-5%) graphene is added as aparticulate component.

Any of the aspects and embodiments described herein can be combined withany other aspect or embodiment as disclosed here in the Summary of theInvention, in the Drawings, and/or in the Detailed Description of theInvention, including the below specific, non-limiting,examples/embodiments of the present invention.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this application belongs. In the specification, thesingular forms also include the plural unless the context clearlydictates otherwise.

Although methods and materials similar to or equivalent to thosedescribed herein can be used in the practice and testing of theapplication, suitable methods and materials are described below. Allpublications, patent applications, patents, and other referencesmentioned herein are incorporated by reference.

The references cited herein are not admitted to be prior art to theclaimed application. In the case of conflict, the present specification,including definitions, will control. In addition, the materials,methods, and examples are illustrative only and not intended to belimiting.

Other features and advantages of the application will become apparentfrom the following detailed description in conjunction with theexamples.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1A-1B are radiograph images of application of the flowable pasteformulation of the present disclosure between in thin layers betweenbone surfaces (FIG. 1A) or through cannulated/fenestrated screw (FIG.1B).

DETAILED DESCRIPTION OF THE INVENTION Definitions

In this disclosure, “comprises,” “comprising,” “containing,” “having,”and the like can have the meaning ascribed to them in U.S. Patent lawand can mean “includes,” “including,” and the like; the terms“consisting essentially of” or “consists essentially” likewise have themeaning ascribed in U.S. Patent law and these terms are open-ended,allowing for the presence of more than that which is recited so long asbasic or novel characteristics of that which is recited are not changedby the presence of more than that which is recited, but excludes priorart embodiments.

Unless specifically stated or obvious from context, as used herein, theterms “a,” “an,” and “the” are understood to be singular or plural.

Unless specifically stated or obvious from context, as used herein, theterm “or” is understood to be inclusive.

As used herein, the term “about,” unless indicated otherwise, refers tothe recited value, e.g., amount, dose, temperature, time, percentage,etc., ±10%, ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1%.

As used herein, the terms “patient” or “subject” are usedinterchangeably herein to refer to any mammal, including humans,domestic and farm animals, and zoo, sports, and pet animals, such asdogs, horses, cats, and agricultural use animals including cattle,sheep, pigs, and goats. One preferred mammal is a human, includingadults, children, and the elderly. A subject may also be a pet animal,including dogs, cats and horses. Preferred agricultural animals would bepigs, cattle and goats.

The phrases “therapeutically effective amount” and “effective amount”and the like, as used herein, indicate an amount necessary to administerto a patient, or to a cell, tissue, or organ of a patient, to achieve atherapeutic effect, such as an ameliorating or alternatively a curativeeffect. The effective amount is sufficient to elicit the biological ormedical response of a cell, tissue, system, animal, or human that isbeing sought by a researcher, veterinarian, medical doctor, orclinician. Determination of the appropriate effective amount ortherapeutically effective amount is within the routine level of skill inthe art.

The terms “administering”, “administer”, “administration” and the like,as used herein, refer to any mode of transferring, delivering,introducing, or transporting a therapeutic agent to a subject in need oftreatment with such an agent. Such modes include, but are not limitedto, intraocular, oral, topical, intravenous, intraperitoneal,intramuscular, intradermal, intranasal, and subcutaneous administration.

As used herein, the term “substantially” means greater than 85% (i.e.,greater than 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99,or 100%).

As used herein, the terms “Pluronics” and “polaxmers” are usedinterchangeably herein to refer to nonionic triblock copolymerscontaining a central hydrophobic chain of polyoxypropylene flanked bytwo hydrophilic chains of polyoxyethylene The name of a given Pluronicstarts with a letter to define its physical form at room temperature(L=liquid, P=paste, F=flake (solid)) followed by a two or three digitnumber. The first digit (or two digits in a three-digit number)multiplied by 300 indicates the approximate molecular weight of thehydrophobe, and the last digit multiplied by 10 gives the percentagepolyoxyethylene content.

In 1918, blood plasma was first used for military transfusion purposes.During the second World War, blood was fractionated by separating redand white cells from the plasma that was found to contain many activeproteins such as growth factors, platelets, fibrinogen,immunoregulators, etc. For safety and convenience during the war, theliquid plasma was provided dry and was reconstituted by adding steriledistilled water just before use on the battlefield, thus preserving theplasma's beneficial regenerative protein components.

Plasma-derived implant materials are described, for example, in U.S.Pat. Nos. 8,293,530; 8,529,956; 8,529,958; 8,529,959; 8,529,960;8,529,961; and 8,911,789 (Carmell Therapeutics, Pittsburgh, Pa.), whichare herein incorporated by reference. The present disclosure relates tocurable or settable compositions for use in surgery. Also provided arerelated devices, including surgical kits and packages, as well asmethods of making and using the compositions. The terms settable andcurable are used interchangeably herein. The settable compositionsdescribed herein consist of at least two component parts that areprovided as individual units, each containing reagents in amounts suchthat when the components are combined they form a single homogenouscomposition that is settable and that reacts or cures into a finalhardened form over a period of time. In one embodiment, the mixturecures into a final hardened composition at either room temperature orbody temperature, over a period of time, and without the need to applyadditional external heat in excess of the ambient heat of the room(about 24-26° C. (i.e., 24, 25, or 26° C.)) or the heat of the humanbody (about 37° C.). In one embodiment, the period of time for completecure into a hardened final form is from about 6 to 12 (i.e., 6, 7, 8, 9,10, 11, or 12) hours or from about 6 to 24 hours (i.e., 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24). In oneembodiment, the fully cured composition is drillable or machinable. Inone embodiment, the homogenous composition is thermoplastic and can besoftened to return it to a hand-moldable state by applying heatsufficient to warm the composition to a temperature at least higher than40° C., preferably between 40° C. and 100° C. (i.e., 40, 41, 42, 43, 44,45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62,63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80,81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98,99, or 100° C.). In accordance with this embodiment, where thecomposition sets or cures prematurely during use, it may be heated untilit becomes moldable again for a period of time until it cools.

Provided herein are bone hemostatic and adhesive composition comprisinga first component (also referred to as component A) and a secondcomponent (also referred to as component B), wherein the first componentcomprises a polyfunctional isocyanate compound, one or more polyols, anda particulate component, wherein the second putty comprises apolyfunctional isocyanate compound one or more polyols and a particulatecomponent, wherein the particulate component comprises one or moreparticulate materials, and wherein the first and the second componentsare mixed together to form a bioabsorbable, homogenous putty.

In some embodiments, the first component comprises 30% to 40% of apolyfunctional isocyanate compound, 0% to 3% of one or more polyols, and50%-65% of a particulate component, based upon the total weight of thefirst putty, the second putty comprises 3% to 5% of a polyfunctionalisocyanate compound, 0.5% to 15% of one or more polyols, and 70% to 85%of a particulate component, based upon the total weight of the secondputty, wherein the particulate component comprises one or moreparticulate materials, and wherein the first and the second putties aremixed together to form a bioabsorbable, homogenous putty.

In some embodiments, the first component comprises 30% to 35% of apolyfunctional isocyanate compound, based upon the total weight of thefirst putty, and the second component comprises 3% to 5% of apolyfunctional isocyanate compound, based upon the total weight of thesecond component. In some embodiments, the first component comprises 30%to 35% (i.e., 30% to 31%, 31% to 32%, 32% to 33%, 33% to 34% or 34% to35%) of a polyfunctional isocyanate compound, based upon the totalweight of the first component. In some embodiments, the second componentcomprises 3% to 5% (i.e., 3% to 3.5%, 3.5% to 4%, 4% to 4.5% or 4.5% to5%) of a polyfunctional isocyanate compound, based upon the total weightof the second component.

In some embodiments, the first component comprises 35% to 40% of apolyfunctional isocyanate compound, based upon the total weight of thefirst component, and the second component comprises 3% to 5% of apolyfunctional isocyanate compound, based upon the total weight of thesecond component. In some embodiments, the first component comprises 35%to 40% (i.e., 35%-36%, 36% to 37%, 37% to 38%, 38% to 39% or 39% to 40%)of a polyfunctional isocyanate compound, based upon the total weight ofthe first component. In some embodiments, the second component comprises3% to 5% (i.e., 3% to 3.5%, 3.5% to 4%, 4% to 4.5% or 4.5% to 5%) of apolyfunctional isocyanate compound, based upon the total weight of thesecond component.

In some embodiments, the first component comprises 2% to 3% of one ormore polyols, based upon the total weight of the first putty, and thesecond putty comprises 0.5% to 5% of one or more polyols, based upon thetotal weight of the second putty. In some embodiments, the firstcomponent comprises 2% to 3% (i.e., 2% to 2.2%, 2.2% to 2.4%, 2.4% to2.6%, 2.6% to 2.8% or 2.8% to 3%) of one or more polyols, based upon thetotal weight of the first component, and the second component comprises0.5% to 5% (i.e., 0.5% to 0.6%, 0.6% to 0.7%, 0.7% to 0.8%, 0.8% to0.9%, 0.9% to1%, 1% to 2%, 2% to 3%, 3% to 4%, or 4% to 5%) of one ormore polyols, based upon the total weight of the second component.

In some embodiments, the first component comprises 2% to 3% of one ormore polyols, based upon the total weight of the first component, andthe second component comprises 1.5% to 5% of one or more polyols, basedupon the total weight of the second component. In some embodiments, thefirst component comprises 2% to 3% (i.e., 2% to 2.2%, 2.2% to 2.4%, 2.4%to 2.6%, 2.6% to 2.8% or 2.8% to 3%) of one or more polyols, based uponthe total weight of the first component, and the second componentcomprises 1.5% to 5% (i.e., 1.5% to 1.6%, 1.6% to 1.7%, 1.7% to 1.8%,1.8% to 1.9%, 1.9% to 2%, 2% to 2.1%, 2.1% to 2.2%, 2.2% to 2.3%, 2.3%to 2.4%, 2.4% to 2.5%, 2.5% to 2.6%, 2.6% to 2.7%, 2.7% to 2.8%, 2.8% to2.9% or 2.9% to 3%) of one or more polyols, based upon the total weightof the second component.

In some embodiments, the first component comprises 0% to 2% of one ormore polyols, based upon the total weight of the first component, andthe second component comprises 2% to 10% of one or more polyols, basedupon the total weight of the second component. In some embodiments, thefirst component comprises 0% to 2% (i.e., 0% to 0.1%, 0.1% to 0.2%, 0.2%to 0.3%, 0.3% to 0.4%, 0.4% to 0.5%, 0.5% to 0.6%, 0.7% to 0.8%, 0.8% to0.9%, 0.9% to 1%, 1% to 1.1%, 1.1% to 1,2%, 1.2% to 1.3%, 1.3% to 1.4%,1.4% to 1.5%, 1.5% to 1.6%, 1.6% to 1.7%, 1.7% to 1.8%, 1.8% to 1.9% or1.9% to 2%) of one or more polyols, based upon the total weight of thefirst component, and the second component comprises 2% to 10% (2% to2.5%, 2.5% to 3%, 3% to 3,5%, 3.5% to 4%, 4% to 4.5%, 4.5% to 5%, 5% to5.5%, 5.5% to 6%, 6% to 6.5%, 6.5% to 7%, 7% to 7.5%, 7.5% to 8%, 8% to8.5%, 8.5% to 9%, 9% to 9.5% or 9.5% to 10%) of one or more polyols,based upon the total weight of the second component.

In some embodiments, the first component comprises 0% to 2% of one ormore polyols, based upon the total weight of the first component, andwherein the second component comprises 10% to 15% of one or morepolyols, based upon the total weight of the second component. In someembodiments, the first component comprises 0% to 2% (i.e., 0% to 0.1%,0.1% to 0.2%, 0.2% to 0.3%, 0.3% to 0.4%, 0.4% to 0.5%, 0.5% to 0.6%,0.7% to 0.8%, 0.8% to 0.9%, 0.9% to 1%, 1% to 1.1%, 1.1% to 1.2%, 1.2%to 1.3%, 1.3% to 1.4%, 1.4% to 1.5%, 1.5% to 1.6%, 1.6% to 1.7%, 1.7% to1.8% or 1.8% to 1.9% or 1.9% to 2%) of one or more polyols, based uponthe total weight of the first component, and wherein the secondcomponent comprises 10% to 15% (10% to 10.5%, 10.5% to 11%, 11% to11.5%, 11.5% to 12%, 12% to 12.5%, 12.5% to 13%, 13% to 13.5%, 13.5% to14%, 14% to 14.5% or 14.5% to 15%) of one or more polyols, based uponthe total weight of the second component.

In some embodiments, the first component comprises less than 0.5% of oneor more polyols, based upon the total weight of the first putty, and thesecond putty comprises 0.5 to 15% of one or more polyols, based upon thetotal weight of the second putty. In a preferred embodiment, the firstcomponent comprises 0% of one or more polyols, based upon the totalweight of the first putty.

In some embodiments, the first component comprises 30% to 40% of apolyfunctional isocyanate compound, less than 0.5% of one or morepolyols, and 50-65% of a particulate component, based upon the totalweight of the first putty, the second putty comprises 3% to 5% of apolyfunctional isocyanate compound, 0.5 to 15% of one or more polyols,and 70% to 85% of a particulate component, based upon the total weightof the second putty, wherein the particulate component comprises one ormore particulate materials, and wherein the first and the second puttiesare mixed together to form a bioabsorbable, homogenous putty.

In some embodiments, the first component comprises less than 0.5% of oneor more polyols, based upon the total weight of the first component, andthe second component comprises 2% to 10% of one or more polyols, basedupon the total weight of the second component. In some embodiments, thefirst component comprises less than 0.5% (i.e., 0% to 0.1%, 0.1% to0.2%, 0.2% to 0.3%, 0.3% to 0.4% or 0.4% to 0.49%) of one or morepolyols, based upon the total weight of the first component, and thesecond component comprises 2% to 10% (2% to 2.5%, 2.5% to 3%, 3% to3,5%, 3.5% to 4%, 4% to 4.5%, 4.5% to 5%, 5% to 5.5%, 5.5% to 6%, 6% to6.5%, 6.5% to 7%, 7% to 7.5%, 7.5% to 8%, 8% to 8.5%, 8.5% to 9%, 9% to9.5% or 9.5% to 10%) of one or more polyols, based upon the total weightof the second component.

In some embodiments, the first component comprises less than 0.5% of oneor more polyols, based upon the total weight of the first component, andwherein the second component comprises 10% to 15% of one or morepolyols, based upon the total weight of the second component. In someembodiments, the first component comprises less than 0.5% (i.e., 0% to0.1%, 0.1% to 0.2%, 0.2% to 0.3%, 0.3% to 0.4% or 0.4% to 0.49%) of oneor more polyols, based upon the total weight of the first component, andwherein the second component comprises 10% to 15% (10% to 10.5%, 10.5%to 11%, 11% to 11.5%, 11.5% to 12%, 12% to 12.5%, 12.5% to 13%, 13% to13.5%, 13.5% to 14%, 14% to 14.5% or 14.5% to 15%) of one or morepolyols, based upon the total weight of the second component.

In some embodiments, the first component comprises 60% to 65% of aparticulate component, based upon the total weight of the firstcomponent, and the second component comprises 80% to 85% of aparticulate component, based upon the total weight of the secondcomponent. In some embodiments, the first component comprises 60% to 65%(60% to 61%, 61% to 62%, 62% to 63%, 63% to 64% or 64% to 65%) of aparticulate component, based upon the total weight of the firstcomponent, and the second component comprises 80% to 85% (i.e., 80% to81%, 81% to 82%, 82% to 83%, 83% to 84% or 84% to 85%) of a particulatecomponent, based upon the total weight of the second component.

In some embodiments, the first component comprises 55% to 60% of aparticulate component, based upon the total weight of the firstcomponent, and the second component comprises 80% to 85% of aparticulate component, based upon the total weight of the secondcomponent. In some embodiments, the first component comprises 55% to 60%(i.e., 55% to 56%, 56% to 57%, 57% to 58%, 58% to 59%, or 59% to 60%) ofa particulate component, based upon the total weight of the firstcomponent, and the second component comprises 80% to 85% (i.e., 80% to81%, 81% to 82%, 82% to 83%, 83% to 84% or 84% to 85%) of a particulatecomponent, based upon the total weight of the second component.

In some embodiments, the first component comprises 50% to 55% (50% to51%, 51% to 52%, 52% to 53%, 53% to 54% or 54% to 55%) of a particulatecomponent, based upon the total weight of the first component, and thesecond component comprises 70% to 75% (70% to 71%, 71% to 72%, 72% to73%, 73% to 74% or 74% to 75%) of a particulate component, based uponthe total weight of the second component.

In some embodiments, the homogenous component formed by mixing the firstand the second components, comprises 50% to 75% of a particulatecomponent, based upon the total weight of the homogenous component. Insome embodiments, the homogenous component formed by mixing the firstand the second components, comprises 50% to 74% (i.e., 50% to 52%, 52%to 54%, 54% to 56%, 56% to 58%, 57% to 60%, 60% to 62%, 62% to 64%, 64%to 66%, 66% to 68%, 68% to 70%, 70% to 72%, or 72% to 74%) of aparticulate component, based upon the total weight of the homogenouscomponent.

In some embodiments, the particulate matter is any one of calciumphosphate, siliconized calcium phosphate, substituted calciumphosphates, calcium pyrophosphate, calcium stearate, barium sulfate, acalcium, magnesium, zinc, aluminum or barium salt of lauric acid, acalcium, magnesium, zinc, aluminum or barium salt of myristic acid; acalcium, magnesium, zinc, aluminum or barium salt of palmitic acid, acalcium, magnesium, zinc, aluminum and/or barium salt of stearic acid, acalcium, magnesium, zinc, aluminum or barium salt of arachidic acid, acalcium, magnesium, zinc, aluminum or barium salt of behenic acid,polyethylene glycol (PEG) laurate, PEG stearate, PEG palmitate, PEGbehenate hydroxyapatite, polymethyl methacrylate, glass-ionomer,absorbable phosphate glass, calcium sulfate, tricalcium phosphate,calcium carbonate, magnesium carbonate, aluminum carbonate, ironcarbonate, zinc carbonate, calcium bicarbonate, sodium bicarbonate,demineralized bone, or mineralized bone. In a preferred embodiment, theparticulate component is calcium phosphate, calcium stearate or acombination thereof.

In some embodiments, the particulate component of the first componentcomprises 0% to 1% of calcium stearate, and 53% to 62% of calciumphosphate, based upon the total weight of the first component, and theparticulate component of the second component comprises 0.1% to 0.5% ofcalcium stearate, and 70% to 84% of calcium phosphate, based upon thetotal weight of the second component. In some embodiments, theparticulate component of the first component comprises 0% to 1% (0% to0.1%, 0.1% to 0.2%, 0.2% to 0.3%, 0.3% to 0.4%, 0.4% to 0.5%, 0.5% to0.6%, 0.6% to 0.7%, 0.7% to 0.8%, 0.8% to 0.9% or 0.9% to 1%) of calciumstearate, and 53% to 62% (53% to 54%, 54% to 55%, 55% to 56%, 56% to57%, 57% to 58%, 58% to 59%, 59% to 60%, 60% to 61% or 61% to 62%) ofcalcium phosphate, based upon the total weight of the first component,and the particulate component of the second component comprises 0.1% to0.5% of calcium stearate (0.1% to 0.2%, 0.2% to 0.3%, 0.3% to 0.4% or0.4% to 0.5%), and 70% to 84% (70% to 71%, 71% to 72%, 72% to 73%, 73%to 74%, 74% to 75%, 75% to 76%, 76% to 77%, 77% to 78%, 78% to 79%, 79%to 80%, 80% to 81%, 81% to 82%, 82% to 83%, 83% to 84%) of calciumphosphate, based upon the total weight of the second component.

In some embodiments, the homogenous composition formed by mixing thefirst and the second components, comprises 0.2% to 1% (0.2% to 0.3%,0.3% to 0.4%, 0.4% to 0.5%, 0.5% to 0.6%, 0.6% to 0.7%, 0.7% to 0.8%,0.8% to 0.9% or 0.9% to 1%) of calcium stearate, and 56% to 73% (56% to57%, 57% to 58%, 58% to 59%, 59% to 60%, 60% to 61%, 61% to 62%, 62% to63%, 63% to 64%, 64% to 65%, 65% to 66%, 66% to 67%, 67% to 68%, 68% to69%, 69% to 70%, 70% to 71%, 71% to 72% or 72% to 73%) of calciumphosphate, based upon the total weight of the homogenous composition.

In some embodiments, the particulate material of the first componentcomprises barium sulfate, calcium stearate, calcium phosphate or acombination thereof. In some embodiments, the particulate material ofthe first component comprises 1% to 10% (i.e., 1% to 1.5%, 1.5% to 2%,2% to 2.5%, 2.5% to 3%, 3% to 3.5%, 3.5% to 4%, 4% to 4.5%, 4.5% to 5%,5% to 5.5%, 5.5% to 6%, 6% to 6.5%, 6.5% to 7%, 7% to 7.5%, 7.5% to 8%,8% to 8.5%, 8.5% to 9%, 9% to 9.5% or 9.5% to 10%) of barium sulfate, 1%to 2% (i.e., 1% to 1.25%, 1.25% to 1.5%, 1.5% to 1.75% or 1.75% to 2%)of calcium stearate and 48% to 53% (i.e., 48% to 49%, 49% to 50%, 50% to51%, 51% to 52% or 52% to 53%) of calcium phosphate, based upon thetotal weight of the first component, and the second component comprises0.1% to 0.5% (0.1% to 0.2%, 0.2% to 0.3%, 0.3% to 0.4% or 0.4% to 0.5%)of calcium stearate and 70% to 75% (i.e., 70% to 71%, 71% to 72%, 72% to73%, 73% to 74% or 74% to 75%) of calcium phosphate, based upon thetotal weight of the second component.

In some embodiments, the homogenous composition formed by mixing thefirst and the second component, comprises 0.5% to 8.5% (i.e., 0.5% to0.6%, 0.6% to 0.7%, 0.7% to 0.8%, 0.8% to 0.9%, 0.9% to 1%, 1% to 1.5%,1.5% to 2%, 2% to 2.5%, 2.5% to 3%, 3% to 3.5%, 3.5% to 4%, 4% to 4.5%,4.5% to 5%, 5% to 5.5%, 5.5% to 6%, 6% to 6.5%, 6.5% to 7%, 7% to 7.5%,7.5% to 8% or 8% to 8.5%) of barium sulfate, 0.2% to 1% of calciumstearate (i.e., 0.2% to 0.3%, 0.3% to 0.4% or 0.4% to 0.5%, 0.5% to0.6%, 0.6% to 0.7%, 0.7% to 0.8%, 0.8% to 0.9% or 0.9% to 1%) and 50% to65% of calcium phosphate (50% to 52%, 52% to 54%, 54% to 56%, 56% to58%, 58% to 60%, 60% to 62% or 62% to 65%) based on the weight of thehomogenous composition.

In some embodiments, the homogenous component formed by mixing the firstand the second components, as described herein, comprises about 0.1% toabout 5% of one or more additives based upon total weight of thehomogenous component. In some embodiments, the homogenous componentformed by mixing the first and the second components, comprises about0.1% to about 5% (i.e., 0.1% to 0.2%, 0.2% to 0.3%, 0.3% to 0.4%, 0.4%to 0.5%, 0.5% to 0.6%, 0.6% to 0.7%, 0.7% to 0.8%, 0.8% to 0.9%, 0.9% to1%, 1% to 1.5%, 1.5% to 2%, 2% to 2.5%, 2.5% to 3%, 3% to 3.5%, 3.5% to4%, 4% to 4.5% or 4.5% to 5%) of one or more additives based upon totalweight of the homogenous component.

In some embodiments, the homogenous component formed by mixing the firstand the second components, comprises about 0.9% to about 5% of one ormore additives, based upon the total weight of the homogenous component.In some embodiments, the homogenous component formed by mixing the firstand the second components, comprises about 0.9% to about 5% (i.e., 0.9%to 1%, 1% to 1.5%, 1.5% to 2%, 2% to 2.5%, 2.5% to 3%, 3% to 3.5%, 3.5%to 4% , 4% to 4.5% or 4.5% to 5%) of one or more additives, based uponthe total weight of the homogenous component.

In some embodiments, the homogenous component formed by mixing the firstand the second components, comprises about 1% to about 5% of one or moreadditives, based upon the total weight of the homogenous component. Insome embodiments, the homogenous component formed by mixing the firstand the second components, comprises about 1% to about 5% (i.e., 1% to1.5%, 1.5% to 2%, 2% to 2.5%, 2.5% to 3%, 3% to 3.5%, 3.5% to 4%, 4% to4.5%, or 4.5% to 5%) of one or more additives, based upon the totalweight of the homogenous component. As used herein, the term “about,”unless indicated otherwise, refers to the recited value, e.g., amount,dose, temperature, time, percentage, etc., ±10%, ±9%, ±8%, ±7%, ±6%,±5%, ±4%, ±3%, ±2%, or ±1%.

In some embodiments, the one or more additives is any one of anantioxidant, a colorant, a steroid, tocopheryl acetate, or triacetin ora combination thereof.

In some embodiments, the first component comprises 0% of triacetin,based upon the total weight of the first component, and the secondcomponent comprises about 0.5% to about 2% of triacetin, based upon thetotal weight of the second component. In some embodiments, the firstcomponent comprises 0% of triacetin, based upon the total weight of thefirst component, and the second component comprises about 0.5% to about2% (0.5% to 0.6%, 0.6% to 0.7%, 0.7% to 0.8%, 0.8% to 0.9%, 0.9% to 1%,1% to 1.1%, 1.1% o 1.2%, 1.2% to 1.3%, 1.3% to 1.4%, 1.4% to 1.5%, 1.5%to 1.6%, 1.6% to 1.7%, 1.7% to 1.8%, 1.8% to 1.9% or 1.9% to 2%) oftriacetin, based upon the total weight of the second component.

In some embodiments, the homogenous component formed by mixing the firstand the second components, comprises about 0.1% to about 1% triacetin,based upon the total weight of the homogenous component. In someembodiments, the homogenous component formed by mixing the first and thesecond component, comprises about 0.1% to about 1% (0.1% to 0.2%, 0.2%to 0.3%, 0.3% to 0.4%, 0.4% to 0.5%, 0.5% to 0.6%, 0.6% to 0.7%, 0.7% to0.8%, 0.8% to 0.9% or 0.9% to 1%) of triacetin, based upon the totalweight of the homogenous component.

In some embodiments, the first component comprises about 6% to about 7%of tocopheryl acetate, based upon the total weight of the firstcomponent, and the second component comprises about 0% to about 4% oftocopheryl acetate, based upon the total weight of the second component.In some embodiments, the first component comprises about 6% to about 7%(6% to 6.1%, 6.1% to 6.2%, 6.2% to 6.3%, 6.3% to 6.4%, 6.4% to 6.5%,6.5% to 6.6%, 6.6% to 6.7%, 6.7% to 6.8%, 6.8% to 6.9% or 6.9% to 7%) oftocopheryl acetate, based upon the total weight of the first component,and the second component comprises about 0% to about 4% (0% to 0.5%,0.5% to 1%, 1.5% to 2%, 2% to 2.5%, 2.5% to 3%, 3% to 3.5%, 3.5% to 4%)of tocopheryl acetate, based upon the total weight of the secondcomponent.

In some embodiments, the homogenous component formed by mixing the firstand the second components, comprise about 5% to about 6% of tocopherylacetate, based upon the total weight of the homogenous putty. In someembodiments, the homogenous component formed by mixing the first and thesecond components, comprise about 5% to about 6% (5% to 5.1%, 5.1% to5.2%, 5.2% to 5.3%, 5.3% to 5.4% or 5.4% to 5.5%, 5.5% to 5.6%, 5.6% to5.7%, 5.7% to 5.8%, 5.8% to 5.9% or 5.9% to 6%) of tocopheryl acetate,based upon the total weight of the homogenous components.

In some embodiment, the polyfunctional isocyanate compound is anaromatic isocyanate, an aliphatic isocyanate, a cycloaliphaticisocyanate, and an adduct of an isocyanate. In some embodiments, thepolyfunctional isocyanate compound is any one of an absorbable lactidediester (ALD), ethyl lysine diisocyanate, cyclohexyl diisocyanate,hexamethylene diisocyanate, a hexamethylene diisocyanate trimer, ahexamethylene diisocyanate biuret, a methylene bis-diphenyldiisocyanate,a lysine diisocyanate, a diphenylmethanediisocyanate (MDI),4,4-diphenylmethanediisocyanate, a mixture of2,4′-diphenylmethanediisocyanate and 4,4′-diphenylmethanediisocyanateisomers, a polycarbodiimide-modified diphenylmethane disocyanate,polymethylene polyphenylisocyanate. In a preferred embodiment, thepolyfunctional isocyanate compound is an absorbable lactide diester(ALD).

In some embodiments, the one or more polyols is any one of ethyleneglycol, diethylene glycol, propanediol, 1,2-propanediol (propyleneglycol), 1,3-propanediol, 1,2-ethanediol (ethylene glycol), butanediol,1,4-butanediol, 1,5-pentanediol, 1,3-cyclopentanediol, 1,6-hexanediol,1,8-octanediol, polytetramethylene ether glycols, polyols derived fromglycolide, lactide, trimethylenecarbonate, p-dioxanone, polycaprolactonepolyol, polycaprolactone triol polyester polyol, polyadipate polyol,diol, poly(butane-adipate) diol, poly(ethylene/propylene-adipate) diol,poly(hexane/adipate/isophthalate diol)), poly(oxypropylene) glycol,poly(oxytetramethylene) glycol, and poly(oxyethylene) glycols,polycaprolactone co-glycolide, a polycaprolactone co-lactide or atriethanolamine (TEOA) or a combination thereof. In a preferredembodiment, the one or more polyols is a polycaprolactone triol, abutanediol or a triethanolamine (TEOA) or a combination thereof.

In some embodiments, the homogenous component formed by mixing the firstand the second components, comprises 20% to 40% of a polyurethanecopolymer, based upon the total weight of the homogenous component. Insome embodiments, the homogenous component formed by mixing the firstand the second components, comprises 20% to 40% (i.e., 20% to 22%, 22%to 24%, 24% to 26%, 26% to 28%, 28% to 30%, 30% to 32%, 32% to 34%, 34%to 36%, 36% to 38% or 38% to 40%) of a polyurethane copolymer, basedupon the total weight of the homogenous component.

In some embodiments, the homogenous component formed by mixing the firstand the second components, comprise a polyurethane co-polymer comprisingof an Absorbable Lactide Diester (ALD)—Polycaprolactone Triol(PCL)—Butanediol (BDO)—Triethanolamine (TEOA) polymer (ALD-PCL-BDO-TEOApolymer). In some embodiments, the homogenous putty formed by mixing thefirst and the second compositions, comprise a polyurethane co-polymercomprising of an Absorbable Lactide Diester-PolycaprolactoneTriol-Butanediol (ALD-PCL-BDO) polymer.

In some embodiments, the bone hemostatic and adhesive compositiondescribed herein comprises a first component and a second component,wherein the first component comprises 30% to 35% of a polyfunctionalisocyanate compound, 0% to 2% of one or more polyols, and 60%-65% of aparticulate component, based upon the total weight of the firstcomponent, wherein the second component comprises 3% to 5% of apolyfunctional isocyanate compound, 1 to 5% of one or more polyols, and80% to 85% of a particulate component, based upon the total weight ofthe second component, wherein the particulate component comprises one ormore particulate matters, and wherein the first and the secondcomponents are mixed together to form a bioabsorbable, and homogenouscomponent.

In some embodiment, the bone hemostatic and adhesive compositiondescribed herein comprises a first component and a second component,wherein the first component comprises 30% to 35% of a polyfunctionalisocyanate compound, 0% to 3% of one or more polyols, 55%-60% of aparticulate component, based upon the total weight of the firstcomponent, wherein the second component comprises 3% to 5% of apolyfunctional isocyanate compound, 0.5% to 5% of one or more polyols,and 80% to 85% of a particulate component, based upon the total weightof the second component, wherein the particulate component comprises oneor more particulate matters, and wherein the first and the secondcomponents are mixed together to form a bioabsorbable, and homogenouscomponent.

In some embodiment, the bone hemostatic and adhesive compositiondescribed herein comprises a first putty and a second putty, wherein thefirst putty comprises 35% to 40% of a polyfunctional isocyanatecompound, and 50%-55% of a particulate component, based upon the totalweight of the first putty, wherein the second putty comprises 3% to 5%of a polyfunctional isocyanate compound, 2% to 12% of one or morepolyols, and 70% to 75% of a particulate component, based upon the totalweight of the second putty, wherein the particulate component comprisesone or more particulate matters, and wherein the first and the secondputties are mixed together to form a bioabsorbable, homogenous putty.

In some embodiments, the composition provided herein has mechanicalproperties suitable for drilling and/or accepting a surgical screwwithout shattering or splintering. In some embodiments, the compositionprovided herein can be used in combination with a surgical hardware,e.g. a screw, a mesh, a plate, a wire, a rod or a nail, wherein thecomposition is used as an adhesive to keep the surgical hardware incontact with a bone. In one embodiment, the composition provided hereincan be used in combination with a surgical hardware, e.g. a screw, aplate, a mesh, a wire, a rod or a nail, wherein the composition is usedas a material to drill, affix or insert the surgical hardware. In someembodiments, the surgical hardware can be a cannulated surgicalhardware, wherein the cannulation of the surgical hardware comprises thecomposition disclosed herein. In some embodiments, the cannulatedsurgical hardware can comprise at least one fenestration to allow thecomposition to extrude from the cannulation of the surgical hardwareinto the surrounding bone.

Provided herein, is a cannulated bone screw having a shaft, a tip, and ahead, at least a portion of said shaft having threads thereon configuredto be inserted into a bone, wherein the screw comprises a cannulationalong the shaft comprising an amount of the homogenous compositiondisclosed herein within the cannulation, and at least one fenestrationdisposed along the shaft of the screw and connected to the cannulationof the screw, wherein the fenestration allows the composition to passthrough the at least one fenestration of the screw into a bone.

In some embodiments, the cannulated bone screw can be configured forinsertion into a hole drilled in a bone. In some embodiments, thecannulated bone screw can be configured for securing in the hole drilledin a bone by an amount of the composition disclosed herein that iscontact with the outer surface of the screw and the walls of the hole.In some embodiments, the cannulated bone screw can be configured forsecuring into a bone by a surgical plate. In some embodiments, thecannulated bone screw can be configured for securing into a bone by atleast one surgical nail. In some embodiments, the cannulated bone screwcan be configured for securing to the bone by a nut or a washer.

In some embodiments, the cannulated bone screw can be for use infracture line reduction between two or more pieces of a bone. In someembodiments, the site of the bone can be a surgical site or a site ofinjury.

In some embodiments, the bone screw can be for use in a method of bonesurgery. In some embodiments, the method of bone surgery can be asurgery of the bone of a jaw, hip, pelvis, knee, ankle, and foot. Insome embodiments, the method of bone surgery can be a surgery ofphalanx, metacarpals, radius, ulna, fibula, femur, clavicle, humerus,tibia, scapula, vertebra, pelvis or rib. In some embodiments, the methodof bone surgery can be arthroscopy, joint replacement, revision jointsurgery, bone fracture repair, debridement, fusion of bones, spinefusion or Osteotomy. In some embodiments, the method of bone surgery canbe ankle fracture repair, knee arthroscopy, knee replacement, repair offemoral neck fracture and trochanteric fracture, hip replacement, wristbone (distal radius) fracture repair, Shoulder arthroscopy, laminectomy,lumbar spinal fusion, low back intervertebral disc surgery, forearm(radius) bone fracture repair, thigh bone (femoral shaft) fracturerepair, or an orthodontic surgery.

In some embodiments, the cannulated bone screw can be used for: joiningtwo pieces of a fractured bone, for securing a surgical hardware e.g., aplate, a rod or a cap or a replacement thereof to a bone, formaintaining or positioning one or more bones in a desired anatomicalposition or orientation.

In some embodiments, the cannulated bone screw can be a cortical screw,a cancellous screw or a Herbert screw. In some embodiments, thecannulated bone screw can be a dynamic hip screw, acutrak screw,malleolar screw, a locking bolt screw, an interference screw or apedicle. In some embodiments, the cannulated bone screw can furthercomprise a central opening in the outer end of the head of the screwconfigured to for receiving a driving tool for driving the screw intothe bone, and for receiving the homogenous composition. In someembodiments, the head of the cannulated bone screw can be threaded,hexagonal or crossed. In some embodiments, the head of the cannulatedbone screw can be threaded. In some embodiments, the head of thecannulated bone screw can be hexagonal. In some embodiments, the head ofthe cannulated bone screw can be crossed.

In some embodiments, the head of the cannulated bone screw can have arecess of about 2.5 mm to about 4 mm. In some embodiments, the head ofthe cannulated bone screw can have a recess of 2.5 mm to 4 mm. In someembodiments, the head of the cannulated bone screw can have a recess of2.5 mm to 3 mm. In some embodiments, the head of the cannulated bonescrew can have a recess of 3 mm to 3.5 mm. In some embodiments, the headof the cannulated bone screw can have a recess of 3.5 mm to 4 mm. Insome embodiments, the head of the cannulated bone screw can have arecess of 2.5 mm. In some embodiments, the head of the cannulated bonescrew can have a recess of 2.8 mm. In some embodiments, the head of thecannulated bone screw can have a recess of 3 mm. In some embodiments,the head of the cannulated bone screw can have a recess of 3.25 mm. Insome embodiments, the head of the cannulated bone screw can have arecess of 3.5 mm. In some embodiments, the head of the cannulated bonescrew can have a recess of 3.75 mm. In some embodiments, the head of thecannulated bone screw can have a recess of 4 mm.

In some embodiments, the tip of the cannulated bone screw disclosedherein can be non-self-tapping, self-tapping, self-drilling or selftapping and self drilling. A “self-tapping” and “a self-drilling” bonescrew as described herein means that the tip of the screw will make ordrill a hole and will cut the channel for the thread.

In some embodiments, the cannulated bone screw can have a thread pitchbetween 9.0 (thread per inch) TPI to 40 TPI. In some embodiments, thecannulated bone screw can have a thread pitch between 9.0 TPI to 20 TPI.In some embodiments, the cannulated bone screw can have a thread pitchbetween 20 TPI to 30 TPI. In some embodiments, the cannulated bone screwcan have a thread pitch between 30 TPI to 40 TPI. The term “threadpitch” as used herein means the number of threads present per inch ofthe screw.

In some embodiments, the cannulated bone screw can have a length ofabout 8 mm to about 150 mm. In some embodiments, the cannulated bonescrew can have a length of 8 mm to 150 mm. In some embodiments, thecannulated bone screw can have a length of 8 mm to 20 mm. In someembodiments, the cannulated bone screw can have a length of 20 mm to 30mm. In some embodiments, the cannulated bone screw can have a length of30 mm to 40 mm. In some embodiments, the cannulated bone screw can havea length of 40 mm to 50 mm. In some embodiments, the cannulated bonescrew can have a length of 50 mm to 75 mm. In some embodiments, thecannulated bone screw can have a length of 75 mm to 80 mm. In someembodiments, the cannulated bone screw can have a length of 80 mm to 100mm. In some embodiments, the cannulated bone screw can have a length of100 mm to 125 mm. In some embodiments, the cannulated bone screw canhave a length of 125 mm to 150 mm.

In some embodiments, the cannulated bone screw can have an outerdiameter of about 3.5 mm to about 7.5 mm. In some embodiments, thecannulated bone screw can have an outer diameter of 3.5 mm to 7.5 mm(i.e., 3.5 to 4 mm, 3.5-3.75 mm, 3.75 mm-4 mm) and a shaft diameter of2.0 mm to 5.0 mm (i.e., 2.0 mm to 2.5 mm, 2.5 mm to 3.0 mm, 3.0 to 3.5mm or 3.5 mm to 4.0 mm).

In some embodiments, the cannulated bone screw bone screw can be made oftitanium, stainless steel or a bioabsorbable material. In someembodiments, the bioabsorbable material is polylactic acid, polyglycolicacid, poly-L-lactic acid or polylactic acid and tricalcium phosphate.

In some embodiments, the cannulated bone screw can be inserted into abone of a hip, pelvis, knee, ankle, and foot. In some embodiments, thecannulated bone screw can be inserted into a bone or portion of phalanx,metacarpals, radius, ulna, fibula, femur, clavicle, humerus, tibia,scapula, vertebra, pelvis or rib.

Provided herein is a method of delivering a bone hemostatic and adhesivecomposition into a site in a bone of a patient in need thereof, themethod comprising: a) providing the cannulated bone screw disclosedherein; b) inserting the cannulated bone screw into the bone of thepatient; and c) allowing the amount of the composition within the bonescrew to be delivered into the bone.

In some embodiments, the step of providing the cannulated bone screwdisclosed herein further comprises delivering an amount of thecomposition disclosed herein, into the cannulation of the bone screw. Insome embodiments, the delivering of an amount of the compositiondisclosed herein into the cannulation can be done by means of a syringe,wherein the syringe is connected to the central opening in the outer endof the head of the screw. In some embodiments, the delivering of anamount of the composition disclosed herein into the cannulation of thecannulated bone screw can be done from a reservoir that is connected tothe central opening in the outer end of the head of the screw by meansof a pump.

In some embodiments, the inserting the cannulated bone screw into thebone of the patient can be done by drilling the screw into the bone. Insome embodiments, inserting the cannulated bone screw into the bone ofthe patient can be done by (i) drilling a hole in the bone of thepatient; (ii) filling the hole with a composition disclosed herein;(iii) allowing the composition in the drilled hole of the bone tosolidify; and (iv) inserting the screw disclosed herein through thesolidified composition in the drilled hole of the bone.

In some embodiments, the inserting of the cannulated bone screw into thebone of the patient can be done by means of an orthopedic screwdriver,an orthopedic electric drilling device, an orthopedic mechanicaldrilling device, an orthopedic tap handle, a bone mallet, or equivalentthereof.

In some embodiments, the inserting of the cannulated bone screw into thebone of the patient can be done by placing a surgical plate between thescrew and the bone. In some embodiments, the inserting of the cannulatedbone screw into the bone of the patient can be done by placing asurgical washer or a nut between the screw and the bone. In someembodiments, the inserting of the cannulated bone screw into the bone ofthe patient can be done by using a surgical guide wire with the bonescrew.

In some embodiments, the inserting of the cannulated bone screw into thebone of the patient further comprises securing the screw in the bone bymeans of at least one surgical nail.

In some embodiments, the method of delivering a bone hemostatic andadhesive composition into a site in a bone disclosed herein, furthercomprises delivering additional amounts of the composition disclosedherein into the cannulation of the bone screw after inserting the bonescrew into the bone. In some embodiments, the method of delivering abone hemostatic and adhesive composition into a site in a bone disclosedherein, can be carried out in combination with a method of bone surgery.In some embodiments, the method of bone surgery can be a surgery of thebone of a jaw, hip, pelvis, knee, ankle, and foot. In some embodiments,the method of bone surgery can be a surgery of phalanx, metacarpals,radius, ulna, fibula, femur, clavicle, humerus, tibia, scapula,vertebra, pelvis or rib. In some embodiments, the method of bone surgerycan be arthroscopy, joint replacement, revision joint surgery, bonefracture repair, debridement, fusion of bones, spine fusion orosteotomy. In some embodiments, the method of bone surgery can be anklefracture repair, knee arthroscopy, knee replacement, repair of femoralneck fracture and trochanteric fracture, hip replacement, wrist bone(distal radius) fracture repair, Shoulder arthroscopy, laminectomy,lumbar spinal fusion, low back intervertebral disc surgery, forearm(radius) bone fracture repair, thigh bone (femoral shaft) fracturerepair or an orthodontic surgery.

In some embodiment, the composition of the present disclosure can be foruse in a method of securing a surgical hardware into a bone of a subjectin need thereof, wherein the surgical hardware has a body and an openingat a point of the body, wherein the surgical hardware is cannulatedinside the body of the hardware, and comprises at least one fenestrationalong the body of the hardware for receiving the composition, whereinthe method comprises: a) inserting the surgical hardware into a site onthe bone; b) delivering the composition hardware inside through theopening into the cannulation in the body of the surgical hardware; c)allowing the composition to pass through the fenestration of thesurgical hardware into an area surrounding the hardware in the bone; andd) allowing the composition to harden to secure the surgical hardware tothe bone. In some embodiments, the surgical hardware can be a screw, aplate, a mesh, a wire, a rod or a nail or equivalent thereof.

In some embodiments of the method of securing a surgical hardware into abone of a subject in need thereof, the method further comprises applyingthe mixed or kneaded composition to the surfaces of the bone fracture orthe cut surfaces of the sternotomy through a surgical mesh to create acap or a flap, and manually reducing or reapproximating the bonefragments while allowing the composition to set; and allowing thecomposition to harden into its fully cured solid form. In someembodiments of the method of securing a surgical hardware into a bone ofa subject in need thereof, the method further comprises customizing theplate or flap by cutting or otherwise machining the mesh prior to orafter the non-absorbable composition is applied to the mesh or flap.

In some embodiments, the first component, the second component and thehomogenous composition formed by mixing the first and the secondcomponents are a putty. In some embodiments, the homogenous compositionformed by mixing the first and the second components is moldable orhand-settable.

In some embodiments, the first component, the second component and thehomogenous composition formed by mixing the first and the secondcomponents are a paste. In some embodiments, the homogenous compositionformed by mixing the first and the second components is a flowablepaste.

In some embodiments, the homogenous composition is formed by mixing from1 part to 5 parts (1 part to 1.5 parts, 1.5 parts to 2 parts, 2 parts to2.5 parts, 2.5 parts to 3 parts, 3 parts to 3.5 parts, 3.5 parts to 4parts, 4 parts to 4.5 parts or 4.5 parts to 5 parts) of the firstcomponent and 1 part of the second component.

In one embodiment, the individual components are sterile.

In one embodiment, an optional chain extender, such as a diol ordiamine, or a crosslinker, such as a triol or triamine, is added to oneof the component parts before combining, or to the homogenous settablecompositions formed from the combining of the component parts, in anamount sufficient to increase the rate of the curing reaction.

In one embodiment, the component parts of a composition described hereare in the form of a putty or paste and may be combined, for example, byhand-kneading, or by extrusion, for example through a syringe, or byotherwise combining or compounding into a single homogenous composition.In one embodiment, the component parts each comprise an additive, suchas a colorant or dye, such that the additives impart a different colorto each component. In one embodiment, the separate additives, each of adifferent color, form a third new color when the components have beenmixed to homogeneity, such that the new color is indicates that a singlehomogenous composition has been formed. In one embodiment, the componentparts consist of part A and part B, part A comprises a colorant or dyewhich gives part A a red color, part B comprises a colorant or dye whichgives part B a blue color, and a composition of a substantially purplecolor is formed from the combination of parts A and B to homogeneity. Inone embodiment, the component parts can be mixed to homogeneity withinabout 1 minute or less, or within about 2 minutes.

In one embodiment, each component of a settable compositions describedherein is in the form of a putty and the homogenous settable compositionthat results from their combination is also in the form of a putty for aperiod of time after initiation of the curing reaction. The term “putty”refers to a composition that is soft, moldable, preferably non-elastic,and cohesive.

In one embodiment, a putty is formed as a suspension or dispersion ofparticulates within a liquid. As an illustrative example of this generalform, one can consider the non-medical putty composition referred to asglaziers putty, which is diatomaceous earth or clay suspended in adrying oil such as linseed oil. In one embodiment, the liquid componentsare selected from liquids such as the polyol, chain extender and thepolyisocyanate. Non-reactive, nontoxic organic liquids such as esters,ethers and hydrocarbons may be employed in this context. In oneembodiment, the solid components are particulate materials selected fromone or more of calcium phosphate, siliconized calcium phosphate, asubstituted calcium phosphate where the substitution is with magnesium,strontium, or silicate, for example, calcium phosphosilicate, calciumpyrophosphate, lyophilized human blood plasma derivatives,hydroxyapatite, barium sulfate, a calcium, magnesium, zinc, aluminum orbarium salt of lauric acid, a calcium, magnesium, zinc, aluminum orbarium salt of myristic acid; a calcium, magnesium, zinc, aluminum orbarium salt of palmitic acid, a calcium, magnesium, zinc, aluminumand/or barium salt of stearic acid, a calcium, magnesium, zinc, aluminumor barium salt of arachidic acid, a calcium, magnesium, zinc, aluminumor barium salt of behenic acid, polyaryletherketone-based materials(e.g., PEK, PEEK, PEKK, PEEKK and PEKEKK), polyurethanes,polyureaurethanes, polymethylmethacrylate (PMMA), silicone polymers,glass-ionomer, absorbable phosphate glass, calcium sulfate, tricalciumphosphate (e.g., beta tricalcium phosphate), demineralized bone matrix(DBM), or mineralized bone, or any combination of the foregoing.

In one embodiment, the particulate component for inclusion in acomponent part of the compositions described here is selected from oneor more of calcium sulfate, sodium phosphate, calcium aluminate,strontium phosphate, calcium strontium phosphate, tricalcium phosphate,calcium pyrophosphate, magnesium phosphate, hydroxyapatite, biomimeticcarbonate apatite, biphasic calcium phosphate/hydroxyapatite,mineralized bone matrix, demineralized bone matrix, glass ionomer,absorbable phosphate glass and nonresorbable particulate metallic orpolymeric materials such as stainless steel or titanium powder ornanoparticles, polyurethane, polyureaurethane, polymethacrylic acid andpolyarylether ketones such as PEK, PEEK, PEKK, PEEKK and PEKEKKparticles. Further examples of particulate materials are provided infra.

The particles of a particulate material used in the component parts ofthe compositions described here may be porous or non-porous particles.In one embodiment, the particles are porous and the degree of porosityis sufficient to permit the ingress of cells or fluids into thecomposition after its placement in situ. Particle size may also bevaried from about 0.05 to less than or equal to 1 millimeter or 2millimeters in diameter to control the consistency, with smallerparticle sizes yielding smoother more cohesive putties.

In one embodiment, the putty consistency is formed by the inclusion ofviscous prepolymers in at least one of the component parts of thecomposition. In this context, a prepolymer comprises reactive componentsthat are liquids and/or powders which are partially reacted by limitingone or more of the reactants to produce more viscous versions of a moreliquid component. Softeners such as nonreactive surfactants, hydrophiliccompounds or polymers such as polyethylene glycol dialkyl ethers, etc.,may also be added.

The settable compositions described herein are biocompatible andsuitable for use in vivo, particularly during surgery. The term“biocompatible” refers to materials that do not induce undesirableeffects when administered or implanted in vivo, for example, an immunereaction and/or an inflammatory reaction, or other adverse reaction thatis detrimental to wound healing and/or to the implant recipient. Abiocompatible material may also be referred to as “nontoxic”. In oneaspect, the biocompatible compositions described here form from alow-exotherm reaction and their formation does not produce toxic fumesor tissue-damaging amounts of heat. In another aspect, where thecompositions are biodegradable, their degradation under physiologicalconditions does not produce toxic by-products and/or is not toxic to theimplant recipient. In one embodiment, the maximum exotherm (amount ofheat i.e., temperature increase, generated by the reaction) of thepolymerization reaction is 20° C. or less, most preferably 10° C. orless.

In one embodiment, the compositions are fully or partiallybiodegradable. The terms “degradable”, “biodegradable”, “resorbable”,and “absorbable” and the like are used interchangeably herein to referto the ability of the claimed compositions to degrade (partially orcompletely) under physiological conditions into non-toxic products thatcan be metabolized or excreted from the body within a period of time,generally several days and up to a year or about 18 to 24 months (i.e.,18, 19, 20, 21, 22, 23, or 24 months) or longer. In one embodiment, thecomposition is fully biodegradable within about 12 months. Compositionsmay be considered non-biodegradable if they remain stable in vivo forperiods exceeding about ten years.

In one embodiment, the compositions are osteopromotive or comprise anosteopromotive component. The term “osteopromotive” encompasses theability to support, enhance or accelerate the growth of new bone tissueby one or more of osteoconduction, and osteoinduction. In oneembodiment, the compositions further comprise one or more osteopromotiverecombinant proteins selected from the group consisting of bonemorphogenic proteins (e.g., BMP-2, BMP-7), platelet derived growthfactor, transforming growth factor beta, epidermal growth factor, NELLand UCB-1. In one embodiment, the osteopromotive component comprises anosteoconductive component. In one embodiment, the osteoconductivecomponent comprises or consists of particles of an osteoconductivematerial, such as particles of tricalcium phosphate or bioglass. Theterm “bioglass” refers to a group of glass-ceramic materials comprisingSiO₂, Na₂O, CaOP₂O₅, and combinations of these. Preferably, theparticles are in a size range of 1 micron to 2,000 microns (e.g.,100-1900, 200-1800, 300-1700, 400-1600, 500-1500, 600-1400, 700-1300,800-1200, or 900-1100 microns) average mean diameter.

In certain embodiments, a homogenous settable composition as describedhere is also mechanically hemostatic. In one embodiment, the homogenoussettable composition has the property of adhering to the surface ofactively bleeding bone with sufficient strength to stop the bleedingwithin at least about 1 minute, at least about 2-5 minutes, or at least5-10 minutes. In accordance with this embodiment, the homogenoussettable composition remains both moldable and sufficiently adhesive toadhere to the surface of actively bleeding bone for a period of timefollowing the combination of component parts that initiated the curingreaction. In one embodiment, the period of time is from about 1 to 30min, about 1 to 15 min, or about 1 to 10 min. In some embodiments, theperiod of time for which the homogenous settable composition remainsboth moldable and sufficiently adhesive following the combination ofcomponent parts that initiated the curing reaction (curing time), can beextended by changing the type and relative amounts of the one or morepolyols in the composition in the homogenous settable composition. Insome embodiments, the curing time can be increased by at least 2 times,by reducing the concentration of 1,4-butanediol (BDO) and increasing theconcentration of polycaprolactone triol (PCL) in the composition in thehomogenous settable composition. In some embodiments, the curing timecan be increased by at least 2 times, by reducing the concentration of1, 4-butanediol (BDO) from 0.75% to 1% of the total weight of the finalcomposition, to 0% to 0.25% of the total weight of the finalcomposition. In some embodiments, the curing time can be increased by atleast 2 times, by reducing the concentration of It should be understoodthat characterizing the adhesive properties of the settable compositionduring a period of time after initiation of the curing reaction inrelation to bleeding bone is meant for descriptive purposes only, andnot intended to limit the use of the compositions to hard tissues. Insome embodiments, the settable compositions described here may also beuseful as soft-tissue hemostats. In addition, although the settablecompositions are described here as having physical properties suitablefor mechanical (tamponade) hemostasis, in certain embodiments any of thehemostatic compositions described herein may also contain one or moreagents that act as active chemical hemostats. Non-limiting examplesinclude blood clot-inducing agents such as prothrombin, thrombin,lyophilized clotted or unclotted human blood plasma optionally processedby crosslinking, oxidized cellulose, microcrystalline collagen, gelatinfoam, collagen sponge, fibrinogen, and fibrin. In one embodiment, thecomposition may also comprise one or more of epinephrine, tannic acid,ferrous sulfate, and the double-sulfates of a trivalent metal and aunivalent metal such as potassium aluminum sulfate and ammonium aluminumsulfate. Thus, a settable composition may be hemostatic, mechanically orchemically, or by a combination of mechanical and chemical hemostasis.

Surgical Kits and Packages

Also provided is a surgical kit or package comprising a settablecomposition described herein. As discussed above, the settablecompositions described herein consist of at least two components thatare provided as individual units, each containing reagents in amountssuch that when the components are mixed, they react or cure into ahardened composition after a period of time, preferably at room or bodytemperature.

As a practical matter, during use of a settable composition in surgery,freshly made material may be required at widely spaced points in time.If the material is not mixed just before use, its moldability,uniformity, and adherence to the surfaces to which it is applied will bediminished. In this context, the adhesive nature of the material is afunction of its uncured state. In some embodiments, the composition asit cures bonds to the tissue at the site of implantation, for examplebone tissue. And if the material is compounded too early, it may setbefore it can be applied. In such a state, it will be insufficientlymoldable, insufficiently adhesive, and unsuitable for use.

The surgical kits and packages described herein provide a solution tothis problem by providing the availability of freshly made settablematerial at different times during a surgical procedure.

In one embodiment, the present disclosure provides a containercomprising two or more compartments, each compartment containing anamount of a component. Where the container comprises multiple sets ofcomponents, the compartments are adapted such that each set can beremoved without disturbing the other sets in the package. If thecomponents are sterile, the container is adapted such that each set ofcomponents can be aseptically removed without compromising the sterilityof the remaining sets. For example, the separate compartments may formthe lower part of a vacuum-formed container with an upper peelable film.The construction of the container allows for the removal of a single setof components from their respective compartments just before use. Thecomponents, thus exposed, then are removed from the container by agloved finger or by using an instrument and are kneaded together untilhomogenous to form a single composition for surgical implantation. Thecomposition thus formed will initially be in a moldable form. In oneembodiment, the composition is in the form of a putty, and thecomponents of each set are also in the form of putties. As thecomposition sets, it hardens into a solid form. When needed, the nextset of compartments in the unit is exposed by peeling down theircovering film and kneading the newly exposed putties together untilhomogeneous and ready for surgical use. In one embodiment, the containercomprises pairs of compartments and the set of components is a pair. Inone embodiment, the container comprises 2 to 12 sets (i.e., 2, 3, 4, 5,6, 7, 8, 9, 10, 11, or 12 sets) of components.

The compartments of the package may be, for example, in the form of adepression or well, or the compartments may comprise walls made of aflexible material having any shape, or an amorphous shape. In oneembodiment in which the package comprises multiple pairs of putties, thepackage may contain any desired number of putty pairs. In oneembodiment, the package consists of 2, 4, 8, 10, or 12 putty pairs. Inone embodiment, perforations may be placed between pairs to facilitateremoval of a pair before or after opening.

In one embodiment the package comprises separate compartments or wellsof a lower, vacuum-formed container with an upper peelable film,designed to allow a single set of putties to be removed from a singleset of compartments as needed, e.g., just before use during surgery. Inone embodiment, the set consists of two and a single package containsfrom 2 to 12 sets (i.e., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 sets) ofputties.

In another embodiment, the package comprises a syringe component. In oneembodiment, the syringe component is a single syringe pre-loaded withmeasured amounts of a set of putties in separate internal compartmentsof the syringe such that when the syringe plunger is depressed, amountsof each component are dispensed or extruded from the syringe to form acomposition that will harden into a final solid (cured) form over aperiod of time at room temperature or body temperature. In oneembodiment, the syringe component comprises two or more syringes, eachpre-loaded with one component of a set. In one embodiment, the setconsists of two components.

In another embodiment, the package comprises separate flexiblecompartments within a flexible plastic container, each compartmenthaving a seal that, when disrupted, allows the contents of thecompartments to mix together into a common flexible plastic compartmentthat is configured to allow mixing of the contents within the commonflexible plastic compartment. In one embodiment, the package is flexibleenough to allow mixing by hand-kneading. In a further embodiment, aftermixing is complete, an orifice is cut into the container to allowremoval of the mixed components.

In one embodiment, the package comprises or consists of a heat sealed orheat sealable foil package. In one embodiment, the package furthercomprises an outer envelope completely surrounding the package, and adesiccant. In one embodiment, the outer envelope is a heat sealed,pinhole free foil package.

In one embodiment, the package comprises a surface which is in contactwith the components, said surface having a surface energy substantiallyequal to or less than the surface energy of the components, or both,such that the component does not adhere or adheres weakly to thesurface. In one embodiment, the surfaces of the package that are incontact with the components are coated with a surface having a surfaceenergy substantially equal to or less than the surface energy of thecomponents such that they do not adhere, or adhere weakly to, thesurface. In one embodiment, the surface is formed of a material selectedfrom the group consisting of polytetrafluoroethylene (PTFE), silicone,polypropylene, polyethylene, and polystyrene.

In certain embodiments, a package has a shelf life of at least 1-2years. In certain embodiments, the package has a shelf life of 6 months,12 months, 18 months, 24 months, or 36 months.

Also provided are methods for making a settable composition, the methodcomprising the steps of providing a package as described herein, thepackage containing a single set or multiple sets of components which,when mixed together, cure into a final hardened composition, and mixinga set of components into a homogenous mass. In another embodiment, themethod comprises the steps of extruding measured amounts of a set fromone or more syringes and kneading them together to form a singlehomogenous mass which cures into a final hardened composition. In oneembodiment, the method comprises the steps of providing a packagecomprising a set of components in separate flexible compartments withina flexible container, the compartments having a breakable seal that,when broken, allows the contents of the compartment to enter into afurther flexible compartment, breaking the seal such that the set ofcomponents enters into the further compartment, mixing the componentsinto a homogenous mass within the further compartment.

As an aid to manipulating the components after extrusion from thesyringe or syringes, or after removal from the packaging, the surgeonmay employ a device having a pliable structure with an applicationsurface having a surface energy substantially equal to or less than thesurface energy of the composition such that the composition does notadhere or adheres very weakly to the device. The device is preferably inthe form of a sheet. Suitable materials for forming the applicationsurface include, for example, polytetrafluoroethylene (PTFE), silicone,polypropylene, polyethylene, and polystyrene. Such devices are describedin US 2012/0035610, which is herein incorporated by reference.

The compositions, packages and methods provided herein are for use insurgical procedures. Preferably, the surgical procedures are practicedon humans, but they may also be used on other mammals such as a dog, acat, a horse, a cow, a pig, or a non-human primate. In one embodiment,the surgical procedure is a procedure for the repair of cranial defectsand cranioplasty applications or for repair and reconstruction of thesternum. In one embodiment, a composition as described herein issuitable for use as a tissue adhesive, a hemostat, a bone cement, or abone void filler.

In one embodiment, a composition, as described herein, is suitable foran orthopedic application as a bone hemostat, a bone adhesive, a bonevoid filler, or a bone cement. The term “bone cement” is meant todistinguish related surgical implants, such as soft tissue adhesives,which may not possess the mechanical properties suitable for use in bonerepair. A bone cement composition, when fully cured, has compressivestrength, tensile strength, and elasticity suitable for use in bonerepair or reconstruction. The solid form also bonds to bone or suitablemetal surfaces and reaches a supporting bond strength within about 90minutes and fully cures within about 24 hours. The solid form furtherbonds with tensile and shear strength comparable with normal bone withinabout 72 hours. In one embodiment, the mixture of putties fully curesinto its solid form at room temperature or body temperature within about90 minutes or about 120 minutes.

In one embodiment, the fully cured composition is suitable for use inbone repair or as a bone cement or bone void filler and has acompressive strength of from 30 to 150 MPa (i.e., 30, 35, 40, 45, 50,55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130,135, 140, 145, or 150 MPa), or greater, a tensile strength of from 20 to80 MPa (i.e., 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80MPa), or greater, and an elasticity defined by a Modulus of Elasticityof from 1,400 to 1,800 MPa (i.e., 1400, 1450, 1500, 1550, 1600, 1650,1700, 1750, or 1800 MPa), or greater. In certain embodiments, thecompressive strength is at least 30 MPa, at least 40 MPa, at least 50MPa, at least 60 MPa, at least 70 MPa, at least 80 MPa, or at least 100MPa. In some embodiments, the compressive strength is greater than 100MPa or greater than 150 MPa. In one embodiment, the compressive strengthis between 100 and 150 MPa (i.e., 100, 105, 110, 115, 120, 125, 130,135, 140, 145, or 150 MPa) or between 150 and 200 MPa (i.e., 150, 155,160, 165, 170, 175, 180, 185, 190, 195, or 200 MPa). Preferably, thesolid form is sufficiently durable to be drillable or machineable. Incertain embodiments the solid form has a tensile strength of at least 20MPa, at least 30 MPa, at least 40 MPa, at least 50 MPa, at least 60 MPa,or at least 80 MPa. In certain embodiments the solid form has a Modulusof Elasticity of at least 1,400 MPa, at least 1,500 MPa, at least 1,600MPa, or at least 1800 MPa. In one embodiment, the solid form has acompressive strength of at least 60 or 70 MPa, a tensile strength of atleast 40 or 50 MPa, and an elasticity of at least 1,600 or 1,800 MPa.

In one embodiment, the fully cured composition is suitable for use insoft tissue and has a compressive strength of from 0 to 25 MPa (i.e., 0,1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,21, 22, 23, 24, or 25 MPa), from 0 to 10 MPa (i.e., 0, 1, 2, 3, 4, 5, 6,7, 8, 9, or 10 MPa), or from 0 to 5 MPa (i.e., 0, 1, 2, 3, 4, or 5 MPa),and a tensile strength of from .005 to 80 MPa (i.e., 0.005, 0.01, 0.015,0.02, 0.025, 0.03, 0.035, 0.040, 0.045, 0.05, 0.055, 0.06, 0.065, 0.07,0.075, 0.08, 0.085, 0.09, 0.095, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4,0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43,44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61,62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79,or 80 MPa), or from 0.005 to 20 MPa (i.e., 0.005, 0.01, 0.015, 0.02,0.025, 0.03, 0.035, 0.040, 0.045, 0.05, 0.055, 0.06, 0.065, 0.07, 0.075,0.08, 0.085, 0.09, 0.095, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45,0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 MPa), or from .005 to15 MPa (i.e., 0.005, 0.01, 0.015, 0.02, 0.025, 0.03, 0.035, 0.040,0.045, 0.05, 0.055, 0.06, 0.065, 0.07, 0.075, 0.08, 0.085, 0.09, 0.095,0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7,0.75, 0.8, 0.85, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15). In certain embodiments, the compressive strength is less than 30MPa, less than 25 MPa, less than 20 MPa, less than 10 MPa, or less than5 MPa.

The mechanical properties described here refer to the properties of thecomposition alone, without the addition of other, optional, materialswhich may further increase these physical properties, especiallycompressive strength. In one embodiment, the compositions describedherein do not comprise an optional particulate material. In certainembodiments, the particulate material, if present, is present in anamount up to about 80% by weight of the composition.

In one embodiment, the compositions are fully or partially degradableunder physiological conditions within a period of time. Where thecompositions are fully degradable, they are degraded within about 12months. The degradation may be enzymatic or non-enzymatic or acombination of both. In one embodiment, the compositions are initiallydegradable into non-toxic products by a non-enzymatic hydrolysis underphysiological conditions. In a preferred embodiment, the compositionsare fully degradable within a period of time less than 12-24 months. Incertain embodiments, the polymer degradation time does not exceed 3months or 6 months. In one embodiment, a composition is degradablewithin about 2 to 4 weeks after placement in vivo. In other embodiments,a composition is fully degradable within about 4 to 6 weeks, or withinabout 2 to 4 months, 4 to 6 months, 6 to 8 months, or 8 to 12 months. Incertain embodiments, the compositions comprise components that are fullydegradable or absorbable. In other embodiments, the compositions arecomprised of components that are partially degradable or absorbable, ornon-degradable. In certain embodiments, the compositions are formed froma combination of fully degradable, partially degradable, and/ornon-degradable components.

Cyanoacrylate- and Methylidene Malonate Ester-Based Compositions

In one embodiment, the settable composition consists of at least twocomponents that, when mixed together, form a mixture that cures into afully hardened polymer composition comprising either methylidenemalonate or alkyl cyanoacrylate esters such as octyl cyanoacrylatepolymers. The first component comprises, for example, eitherdiethylmethylidene malonate or octyl cyanoacrylate monomer, a viscositybuilder such as a minor amount of poly(diethylmethylidine malonate) orpoly(octylcyanoacrylate), a free radical polymerization inhibitorcomponent, e.g., hydroquinone, an acid component to inhibitbased-catalyzed polymerization, e.g., sulfur dioxide and an optionalanhydrous particulate component. The one or more additional componentscomprise the viscosity builder of the first component and, optionally, aparticulate material, and one or more additional optional additives. Inone embodiment, the one or more additional optional additives areselected from a colorant, a therapeutic agent and a radiopaque agent. Inone embodiment, the first putty component comprises a dialkylmethylidene malonate ester and a poly(methylidenemalonate) ester and thesecond putty component comprises a poly(methylidenemalonate) ester andparticles of previously unclotted mammalian blood plasma.

The one or more additional components may further comprise an optionaltherapeutic agent. In one embodiment, the therapeutic agent is selectedfrom one or more of an anti-cancer agent, an antimicrobial agent, anantibiotic, a local anesthetic or analgesic, and an anti-inflammatoryagent.

In one embodiment, the one or more additional components may furthercomprise a bone-growth promoting agent. In one embodiment, the bonegrowth promoting agent is selected from bone morphogenic protein anddemineralized bone matrix, and mixtures thereof. In one embodiment, thebone-growth promoting agent is an osteopromotive recombinant proteinselected from the group consisting of bone morphogenic proteins,platelet derived growth factor, transforming growth factor beta,epidermal growth factor, NELL and UCB-1, and combinations thereof.

In one embodiment, the composition comprises two putty components, A andB; and putty A comprises 20-50% (i.e., 20, 21, 22, 23, 24, 25, 26, 27,28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45,46, 47, 48, 49, or 50% or 20-25, 20-30, 20-35, 20-40, 20-45, 25-30,25-35, 25-40, 25-45, 25-50, 30-35, 30-40, 30-45, 30-50, 35-40, 35-45,35-50, 40-45, 40-50, or 45-50%) of the diethylmethylidene malonate oroctyl cyanoacrylate monomer, 1-15% (i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, or 15% or 1-5, 1-10, 5-10, 5-15, or 10-15%) of theviscosity building component, 0-75% (i.e., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45,46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63,64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, or 75% or 0-5, 0-10, 0-15,0-20, 0-25, 0-30, 0-35,0-40, 0-45, 0-50, 0-55, 0-60, 0-65, 0-70, 5-10,5-15, 5-20, 5-25, 5-30, 5-35, 5-40, 5-45, 5-50, 5-55, 5-60, 5-65, 5-70,5-75, 10-15, 10-20, 10-25, 10-30, 10-35, 10-40, 10-45, 10-50, 10-55,10-60, 10-65, 10-70, 10-75, 15-20, 15-25, 15-30, 15-35, 15-40, 15-45,15-50, 15-55, 15-60, 15-65, 15-70, 15-75, 20-25, 20-30, 20-35, 20-40,20-45, 20-50, 20-55, 20-60, 20-65, 20-70, 20-75, 25-30, 25-35, 25-40,25-45, 25-50, 25-55, 25-60, 25-65, 25-70, 25-75, 30-35, 30-40, 30-45,30-50, 30-55, 30-60, 30-65, 30-70, 30-75, 35-40, 35-45, 35-50, 35-55,35-60, 35-65, 35-70, 35-75, 40-45, 40-50, 40-55, 40-60, 40-65, 40-70,40-75, 45-50, 45-55, 45-60, 45-65, 45-70, 45-75, 50-55, 50-60, 50-65,50-70, 50-75, 55-60, 55-65, 55-70, 55-75, 60-65, 60-70, 60-75, 65-70,65-75, or 70-75%) particulate material, based upon total weight of puttyA, a radical polymerization inhibitor component and an acidicpolymerization inhibitor component; putty B comprises 3- 40% (i.e., 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or40% or 3-5,3-10,3-15,3-20,3-25,3-30, 3-35, 5-10, 5-15, 5-20, 5-25, 5-30,5-35, 5-40, 10-15, 10-20, 10-25, 10-30, 10-35, 10-40, 15-20, 15-25,15-30, 15-35, 15-40, 20-25, 20-30, 20-35, 20-40, 25-30, 25-35, 25-40,30-35, 30-40, or 35-40%) of the viscosity building component, and,optionally, 0-85% (i.e., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31,32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49,50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67,68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, or85% or 0-5, 0-10, 0-15, 0-20, 0-25, 0-30, 0-35,0-40, 0-45, 0-50, 0-55,0-60, 0-65, 0-70, 0-75, 0-80, 5-10, 5-15, 5-20, 5-25, 5-30, 5-35, 5-40,5-45, 5-50, 5-55, 5-60, 5-65, 5-70, 5-75, 5-80, 5-85, 10-15, 10-20,10-25, 10-30, 10-35, 10-40, 10-45, 10-50, 10-55, 10-60, 10-65, 10-70,10-75, 10-80, 10-85, 15-20, 15-25, 15-30, 15-35, 15-40, 15-45, 15-50,15-55, 15-60, 15-65, 15-70, 15-75, 15-80, 15-85, 20-25, 20-30, 20-35,20-40, 20-45, 20-50, 20-55, 20-60, 20-65, 20-70, 20-75, 20-80, 20-85,25-30, 25-35, 25-40, 25-45, 25-50, 25-55, 25-60, 25-65, 25-70, 25-75,25-80, 25-85, 30-35, 30-40, 30-45, 30-50, 30-55, 30-60, 30-65, 30-70,30-75, 30-80, 30-85, 35-40, 35-45, 35-50, 35-55, 35-60, 35-65, 35-70,35-75, 35-80, 35-85, 40-45, 40-50, 40-55, 40-60, 40-65, 40-70, 40-75,40-80, 40-85, 45-50, 45-55, 45-60, 45-65, 45-70, 45-75, 45-80, 45-85,50-55, 50-60, 50-65, 50-70, 50-75, 50-80, 50-85, 55-60, 55-65, 55-70,55-75, 55-80, 55-85, 60-65, 60-70, 60-75, 60-80, 60-85, 65-70, 65-75,65-80, 65-85, 70-75, 70-80, 70-85, 75-80, 75-85, or 80-85%) ofparticulate material, based upon the total weight of putty B, and one ormore optional therapeutic agents or growth promoting agents. In oneembodiment, the viscosity building component comprises polymerizedmonomer, the radical induced polymerization inhibitor componentcomprises or consists of hydroquinone and the acid inducedpolymerization inhibitor component comprises or consists of sulfurdioxide.

In one embodiment, the composition comprises two putty components, A andB, putty A comprising a methylidene malonate ester and apoly(methylidene malonate ester) in amounts ranging from 30 to 70%(i.e., 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45,46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63,64, 65, 66, 67, 68, 69, or 70% or 30-35, 30-40, 30-45, 30-50, 30-55,30-60, 30-65, 35-40, 35-50, 35-55, 35-60, 35-65, 35-70, 40-45, 40-50,40-55, 40-60, 40-65, 40-70, 45-50, 45-55, 45-60, 45-65, 45-70, 50-55,50-60, 50-65, 50-70, 55-60, 55-65, 55-70, 60-65, 60-70, or 65-70%) andputty B comprising poly(methylidenemalonate ester), in amounts rangingfrom 30 to 100% (i.e., 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41,42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59,60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77,78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95,96, 97, 98, 99, or 100% or 30-35, 30-40, 30-45, 30-50, 30-55, 30-60,30-65, 30-70, 30-75, 30-80, 30-85, 30-90, 30-95, 35-40, 35-50, 35-55,35-60, 35-65, 35-70, 35-75, 35-80, 35-85, 35-90, 35-95, 35-100, 40-45,40-50, 40-55, 40-60, 40-65, 40-70, 40-75, 40-80, 40-85, 40-90, 40-95,40-100, 45-50, 45-55, 45-60, 45-65, 45-70, 45-75, 45-80, 45-85, 45-90,45-95, 45-100, 50-55, 50-60, 50-65, 50-70, 50-75, 50-80, 50-85, 50-90,50-95, 50-100, 55-60, 55-65, 55-70, 55-75, 55-80, 55-85, 55-90, 55-95,55-100, 60-65, 60-70, 60-75, 60-80, 60-85, 60-90, 60-95, 60-100, 65-70,65-75, 65-85, 65-90, 65-95, 65-100, 70-75, 70-80, 70-85, 70-90, 70-95,70-100, 75-80, 75-85, 75-90, 75-95, 75-100, 80-85, 80-90, 80-95, 80-100,85-90, 85-95, 85-100, 90-95, 90-100, or 95-100%), wherein the amountsare based upon total weight of the composition. These compositions mayadditionally contain between 10-20% (i.e., 10, 11, 12, 13, 14, 15, 16,17, 18, 19, or 20% or 10-15 or 15-20%) of a lyophilized blood plasmacomponent (e.g., unclotted human pooled or autologous plasma,prescreened for pathogens, and optionally containing trehalose as alyophilization stabilizer, that has been dried by lyophilization orsimple evaporation and then cold-ground or -milled and sieved into auniform particulate form).

In one embodiment, the composition comprises two putty component, thefirst putty comprising a cyanocrylate ester containing at least one freeradical scavenger and one acidifying agent as anti-polymerizationstabilizers and the second putty comprising a poly(cyanoacrylate) esterand particles of previously unclotted mammalian blood plasma.

In one embodiment, the composition comprises two putty components, A andB, putty A comprising or consisting of a cyanoacrylate ester in amountsranging from 30 to 70% (i.e., 30, 31, 32, 33, 34, 35, 36, 37, 38, 39,40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57,58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or 70% or 30-35, 30-40,30-45, 30-50, 30-55, 30-60, 30-65, 35-40, 35-50, 35-55, 35-60, 35-65,35-70, 40-45, 40-50, 40-55, 40-60, 40-65, 40-70, 45-50, 45-55, 45-60,45-65, 45-70, 50-55, 50-60, 50-65, 50-70, 55-60, 55-65, 55-70, 60-65,60-70, or 65-70%)) and a poly (cyanoacrylate) ester in amounts rangingfrom 70 to 30% (i.e., 70, 69, 68, 67, 66, 65, 64, 63, 62, 61, 60, 59,58, 57, 56, 55, 54, 53, 52, 51, 50, 49, 48, 47, 46, 45, 44, 43, 42, 41,40, 39, 38, 37, 36, 35, 34, 33, 32, 31, or 30% or 70-35, 70-40, 70-45,70-50, 70-55, 70-60, 70-65, 65-30, 65-35, 65-40, 65-45, 65-50, 65-55,65-60, 60-30, 60-35, 60-40, 60-45, 60-50, 60-55, 55-30, 55-35, 55-40,55-45, 55-50, 50-30, 50-35, 50-40, 50-45, 45-30, 45-35, 45-40, 40-30,40-35 or 35-30%%) and putty B comprising poly(cyanoacrylate) ester inamounts ranging from 97 to 100% (i.e., 97, 98, 99, or 100% or 97-99,97-100, or 98-100%), wherein the amounts are based upon total weight ofthe composition. Again, these compositions may additionally containbetween 10-20% (i.e., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20% or10-15 or 15-20) of a lyophilized blood plasma component.

Magnesium Phosphate-Based Compositions

In one embodiment, the settable composition consists of at least twocomponents that, when mixed together, form a mixture that cures into afully hardened non-polymeric composition. The first comprises potassiumdihydrogen phosphate, magnesium oxide, and a calcium containing compoundsuch as, e.g., tricalcium phosphate and/or hydroxyapatite(Ca₁₀(PO₄)₆(OH)₂. The first component suspended in one or a mixture ofanhydrous, nontoxic, partially water-miscible, inert suspensionvehicles, for example one or a mixture of two or more of triacetin, aPluronic (poloxamer) such as Pluronic L-35, and acetyl triethyl citrate,or similar liquids. A nontoxic viscosity building agent may be added, ifnecessary. The one or more second component comprises water, and one ora mixture of two or more viscosity building agents. In one embodiment,the viscosity building agent or agents are selected from sodiumcarboxymethyl cellulose, sodium alginate, Carbomer, carrageenan,aluminum silicate (Bentonite), gelatin, collagen, and chitosan. In oneembodiment, the viscosity building agent is present at about 75-85 wt %(i.e., 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, or 85% or 75-80 or80-85%). The second putty component may also optionally comprise aparticulate material. In one embodiment the particulate material isselected from tricalcium phosphate and hydroxyapatite, or mixturesthereof. In one embodiment, the one or more additional second componentsmay also optionally comprise one or more additional additives selectedfrom a colorant, an antioxidant, and a therapeutic agent, for example, astatin.

In one embodiment, the therapeutic agent is selected from one or more ofan anti-cancer agent, an antimicrobial agent, an antibiotic, a localanesthetic or analgesic, a statin and an anti-inflammatory agent. In oneembodiment, the one or more additional component putties may furthercomprise a bone-growth promoting agent.

In one embodiment, the first putty comprises a mixture of potassiumdihydrogen phosphate, magnesium oxide and at least onecalcium-containing compound all suspended in one or a mixture ofanhydrous, non-toxic, partially water-miscible, inert suspensionvehicles and the second putty comprises water, particles of previouslyunclotted mammalian blood plasma, and one or more viscosity-buildingagents.

Isocyanate-Based Compositions

In one embodiment, the settable composition consists of at least twocomponent parts, A and B, that when combined form a composition thatcures into a fully hardened polymeric composition, the polymer selectedfrom a polyurethane, a polyureaurethane, a polyetherurethane, or apolyesterurethane, over a period of time at body temperature (i.e.,about 37 C). At least one of the component parts comprises an isocyanatecomponent and one or both component parts comprise a polyol/polyaminecomponent (for example, the first putty component may comprise apolyfunctional isocyanate, tocopherol acetate, calcium phosphateparticles and a polyol and the second putty component may comprise apolyfunctional isocyanate, calcium phosphate particles, at least onepolyol, a fatty acid salt and tocopherol acetate). The isocyanatecomponent consists of an isocyanate monomer, polymer, prepolymer, orcombination thereof. The isocyanate component may thus comprise one ormore different isocyanates, as well as an isocyanate in both itsmonomeric form and its polymer or prepolymer form. The term “isocyanate”is used generically to refer to isocyanates, diisocyanates, andpolyisocyanates. The term “polyol” in the context of the“polyol/polyamine component” refers to both diols and polyols. Thus, thepolyol or polyamine component may comprise or consist of one or moredifferent diols, polyols, polyamines, or mixtures of two or more diols,polyols and/or polyamines.

In one embodiment, the composition further comprises an additiveselected from one or more of tocopherol esters (e.g., tocopheryl(Vitamin E) acetate (TA)), triglycerides, acetyl triethyl citrate, andfatty acid esters, to aid in handling properties and packaging. In oneembodiment, the composition further comprises one or more additivesselected from an antioxidant, an anhydrous particulate material, acolorant, a therapeutic agent, and a radiopaque agent. In oneembodiment, the therapeutic agent is selected from one or more of ananticancer agent, an antimicrobial agent, an anesthetic agent, ananalgesic agent, an anti-inflammatory agent, and an osteogenic agent.

In one embodiment, the composition further comprises an osteoconductivecomponent. In one embodiment, the osteoconductive component also confersporosity to the composition and the porosity is sufficient to allow theingress of fluids and/or cells (e.g., osteoclasts, blood cells) into thecomposition in situ. In one embodiment, the osteoconductive componentcomprises or consists of particles of an osteoconductive material, suchas particles of tricalcium phosphate or bioglass. The term bioglassrefers to a group of glass-ceramic materials comprising SiO₂, Na₂O,CaOP₂O₅, and combinations of these.

In one embodiment, porosity is not introduced into the composition as itcures by the addition of water or a carboxylic acid, e.g., benzoic acid,into any of the component parts of the composition. In one embodiment,the component parts do not contain either a carboxylic acid or addedwater such that the only water present during the curing reaction iswater that may optionally be present at the site of implantation in thebody.

In one embodiment, the fully hardened polyurethane or polyureaurethanecomposition possesses sufficient mechanical properties to be weightbearing, for example for use as a weight-bearing implant in bone, suchas a bone void filler, or a bone cement.

In one embodiment, one or more of the components of the compositioncomprises a prepolymer. A prepolymer is a polymer having reactive endgroups, e.g., isocyanate or hydroxyl groups. In one embodiment, theprepolymer comprises an excess of the isocyanate component relative tothe polyol/polyamine component. In one embodiment of a two-componentcomposition, one component comprises a prepolymer and no, orsubstantially no, unreacted polyol; and the second comprises or consistsof a hydroxyl terminated prepolymer lacking free isocyanate groups andunreacted polyol or polyamine.

A low molecular weight polymer refers to a polymer having a numberaverage molecular weight in the range of about 500 to 20,000 (i.e., 500,1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 6500,7000, 7500, 8000, 8500, 9000, 9500, 10,000, 10,500, 11,000, 11,500,12,000, 12,500, 13,000, 13,500, 14,000, 14,500, 15,000, 15,500, 16,000,16,500, 17,000, 17,500, 18,000, 18,500, 19,000, 19,500, or 20,000 or500-1,000, 500-5,000, 500-10,000, 500-15,000, 1,000-5,000, 1,000-10,000,1,000-15,000, 1,000-2,0000, 5,000-10,000, 5,000-15,000, 10,000-15,000,10,000-20,000, or 15,000-20,000) or 500 to 10,000 ((i.e., 500, 1000,1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 6500, 7000,7500, 8000, 8500, 9000, 9500, or 10,000 or 500-1,000, 500-5,000,1,000-5,000, 1,000-10,000, or 5,000-10000). A prepolymer containingreactive isocyanate end groups is formed, for example, from the initialreaction of an excess of isocyanate with a limiting amount of polyol orpolyamine.

Each of the components may also independently comprise an optionalparticulate material and an optional chain extender, crosslinker, orcurative. For example, the first putty, the second putty, or both thefirst putty and the second putty may comprise one or more particulatematerials selected from calcium sulfate, calcium phosphosilicate, sodiumphosphate, calcium aluminate, or calcium phosphate. The first putty, thesecond putty, or both the first putty and the second putty may compriseone or more particulate materials selected from apolyaryletherketone-based material, a polymethylmethacrylate-basedmaterial, or a tantalum- or titanium-based filler. The first putty, thesecond putty, or both the first putty and the second putty may compriseone or more particulate materials selected from calcium sulfate, sodiumphosphate, calcium aluminate, strontium phosphate, calcium strontiumphosphate, tricalcium phosphate, calcium pyrophosphate, or magnesiumphosphate. The first putty, the second putty, or both the first puttyand the second putty may comprise one or more particulate materialsselected from absorbable phosphate glass, nonresorbable particulatemetallic materials (e.g. stainless steel powder, titanium powder,stainless steel nanoparticles, or titanium nanoparticles), ornonresorbable polymeric materials (e.g. polyurethane particles,polyureaurethane particles, polymethacrylic acid particles, andpolyarylether ketone particles). The second putty may comprise one ormore particulate materials selected from hydroxyapatite, biomimeticcarbonate apatite, biphasic calcium phosphate/hydroxyapatite,mineralized bone matrix, demineralized bone matrix, or glass ionomer.

As discussed above, the components of the settable composition areprovided as individual units, each containing reagents in amounts suchthat when the components are mixed together, they form a mixture thatfully reacts or cures into a hardened composition after a period of timeat room or body temperature. For example, where the settable compositioncomprises two putties, A and B, putty A comprises an excess of theisocyanate component relative to the polyol component and putty Bcomprises less of the isocyanate component and more of thepolyol/polyamine component than putty A. Putty B also optionallycomprises a chain extender and/or crosslinker. Each putty optionallycontains an amount of particulate material suspended in the liquidcomponents to form a composition having a putty-like consistency.

In one embodiment, the particulate material is selected from one or moreof a polyurethane, calcium sulfate, calcium phosphosilicate, sodiumphosphate, calcium aluminate, calcium phosphate, hydroxyapatite,demineralized bone, or mineralized bone. Other particulate materials mayalso be used, as described infra.

In one embodiment, putty A comprises 15-50% (i.e., 15, 16, 17, 18, 19,20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37,38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50% or 15-20, 15-25,15-30, 15-35, 15-40, 15-45, 20-25, 20-30, 20-35, 20-40, 20-45, 20-50,25-30, 25-35, 25-40, 25-45, 25-50, 30-35, 30-40, 30-45, 30-50, 35-40,35-45, 35-50, 40-45, 40-50, or 45-50%) of the isocyanate component,0.5-5% (i.e., 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6,1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1,3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4., 4.5,4.6, 4.7, 4.8, 4.9, or 5% or 0.5-1, 0.5-1.5, 0.5-2, 0.5-2.5, 0.5-3.0,0.5-3.5, 0.5-4.0, 0.5-4.5,1-1.5, 1-2, 1-2.5, 1-3, 1-3.5, 1-4, 1-4.5,1-5, 1.5-2, 1.5-2.5, 1.5-3, 1.5-3.5, 1.5-4, 1.5-4.5, 1.5-5, 2-2.5, 2-3,2-3.5, 2-4, 2-4.5, 2-5, 2.5-3, 2.5-3.5, 2.5-4, 2.5-4.5, 2.5-5, 3-3.5,3-4, 3-4.5, 3-5, 3.5-4, 3.5-4.5, 3.5-5, 4-4.5, 4-5, or 4.5-5%) of thepolyol component, and 40-85% (i.e., 40, 41, 42, 43, 44, 45, 46, 47, 48,49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66,67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84,or 85% or 40-45, 40-50, 40-55, 40-60, 40-65, 40-70, 40-75, 40-80, 45-50,45-55, 45-60, 45-65, 45-70, 45-75, 45-80, 45-85, 50-55, 50-60, 50-65,50-70, 50-75, 50-80, 50-85, 55-60, 55-65, 55-70, 55-75,55-80, 55-85,60-65, 60-70, 60-75, 60-80, 60-85, 65-70, 65-75, 65-70, 65-75, 65-80,65-85, 70-75, 70-80, 70-85, 75-80, 75-85, or 80-85%) of the polyolcomponent, and 40-75% (i.e., 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50,51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68,69, or 70% or 40-45, 40-50, 40-55, 40-60, 40-65, 40-70, 45-50, 45-55,45-60, 45-65, 45-70, 45-75, 50-55, 50-60, 50-65, 50-70, 50-75, 55-60,55-65, 55-70, 55-75, 60-65, 60-70, 60-75, 65-70, 65-75, or 70-75%)particulate material, based upon total weight of putty A; putty Bcomprises 1-10% (i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10% (i.e., 1, 2, 3,4, 5, 6, 7, 8, 9, or 10%% or 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9,2-3, 2-4, 2-5, 2-6, 2-7, 2-8, 2-9, 2-10, 3-4, 3-5, 3-6, 3-7, 3-8, 3-9,4-5, 4-6, 4-7, 4-8, 4-9, 4-10, 5-6, 5-7, 5-8, 5-9, 5-10, 6-7, 6-8, 6-9,6-10, 7-8, 7-9, 7-10, 8-9, 8-10 or 9-10) of the isocyanate component,3-15% (i.e., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15% (i.e., 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15% or 3-5, 3-10, 5-10, 5-15,or 10-15)) of the polyol component, and 65-85% (i.e., 65, 66, 67, 68,69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, or 85%or 65-70, 65-75, 65-80, 70-75, 70-80, 70-85, 75-80, 75-85, or 80-85%)particulate material, based upon total weight of putty B.

In one embodiment, putty A comprises 20-35% (i.e., 20, 21, 22, 23, 24,25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35% or 20-25, 20-30, 25-30,25-35, or 30-35%) of the isocyanate component, 0.5-5% (i.e., 0.5, 0.6,0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1,2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6,3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4., 4.5, 4.6, 4.7, 4.8, 4.9, or 5% or0.5-1, 0.5-1.5, 0.5-2, 0.5-2.5, 0.5-3.0, 0.5-3.5, 0.5-4.0,0.5-4.5,1-1.5, 1-2, 1-2.5, 1-3, 1-3.5, 1-4, 1-4.5, 1-5, 1.5-2, 1.5-2.5,1.5-3, 1.5-3.5, 1.5-4, 1.5-4.5, 1.5-5, 2-2.5, 2-3, 2-3.5, 2-4, 2-4.5,2-5, 2.5-3, 2.5-3.5, 2.5-4, 2.5-4.5, 2.5-5, 3-3.5, 3-4, 3-4.5, 3-5,3.5-4, 3.5-4.5, 3.5-5, 4-4.5, 4-5, or 4.5-5%) of the polyol component,and 40-85% (i.e., 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52,53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70,71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, or 85% or 40-45,40-50, 40-55, 40-60, 40-65, 40-70, 40-75, 40-80, 45-50, 45-55, 45-60,45-65, 45-70, 45-75, 45-80, 45-85, 50-55, 50-60, 50-65, 50-70, 50-75,50-80, 50-85, 55-60, 55-65, 55-70, 55-75,55-80, 55-85, 60-65, 60-70,60-75, 60-80, 60-85, 65-70, 65-75, 65-70, 65-75, 65-80, 65-85, 70-75,70-80, 70-85, 75-80, 75-85, or 80-85%)) of the polyol component, and50-75% particulate material, based upon total weight of putty A; putty Bcomprises 1-10% (i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10% (i.e., 1, 2, 3,4, 5, 6, 7, 8, 9, or 10% or 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 2-3,2-4, 2-5, 2-6, 2-7, 2-8, 2-9, 2-10, 3-4, 3-5, 3-6, 3-7, 3-8, 3-9, 4-5,4-6, 4-7, 4-8, 4-9, 4-10, 5-6, 5-7, 5-8, 5-9, 5-10, 6-7, 6-8, 6-9, 6-10,7-8, 7-9, 7-10, 8-9, 8-10 or 9-10) of the isocyanate component, 3-15%(i.e., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15% i.e., 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, or 15% or 3-5, 3-10, 5-10, 5-15, or 10-15%)of the polyol component, and 75-85% (i.e., 75, 76, 77, 78, 79, 80, 81,82, 83, 84, or 85% or 75-80 or 80-85%) particulate material, based upontotal weight of putty B.

The Isocyanate Component

In one embodiment, the isocyanate component comprises or consists of anaromatic isocyanate, an aliphatic isocyanate, a cycloaliphaticisocyanate, or an adduct of an isocyanate, or a mixture of any of theforegoing. A mixture refers to a mixture of two or more of theforegoing. For example, the isocyanate component may comprise or consistof a mixture of two or more isocyanates independently selected from anaromatic isocyanate, an aliphatic isocyanate, a cycloaliphaticisocyanate, and an adduct of an isocyanate.

In one embodiment, the isocyanate is an aliphatic isocyanate selectedfrom the group consisting of ethyl lysine diisocyanate, hexamethylenediisocyanate, cyclohexyl diisocyanate.

In one embodiment, the isocyanate component comprises one or moreisocyanates that are relatively non-absorbable. In one embodiment, theisocyanate is an aromatic isocyanate selected fromdiphenylmethanediisocyanate (MDI), including mixtures thereof such asmixtures of 2,4′-diphenylmethanediisocyanate and4,4′-diphenylmethanediisocyanate isomers (ISONATE 50 OP, Dow ChemicalCo. and RUBINATE 9433, Huntsman Corp.) and its pure4,4-diphenylmethanediisocyanate form (MONDUR M, Bayer AG and RUBINATE44, Huntsman Corp.). In one embodiment, the aromatic isocyanate is oneof the commercially available polymeric isocyanates (e.g.,polycarbodiimide-modified diphenylmethane di socyanate (ISONATE 143L)and polymethylene polyphenylisocyanate that contains MDI (ISONATE PAPI901 or ISONATE PAPI 27) (Dow Chemical Co.)). These isocyanates,particularly the diphenylmethane derivatives, generally result innon-absorbable or slowly absorbable polyurethanes.

In embodiments, the isocyanate component comprises or consists of aresorbable lactyl diisocyanate, preferably benzoic acid,4-isocyanato-1,1′-[oxybis[2,1-ethanediyloxy(l-methyl-2-oxo-2,1-ethanediyl)]]ester,referred to herein as absorbable lactide diester (ALD). In oneembodiment in which the composition is fully or partially absorbable,the isocyanate component comprises or consists of[5-[2-[2-(4-Isocyanatobenzoyl)oxypropanoyloxy]-ethoxy]-1-methyl-2-oxo-pentyl]-4-isocyanatobenzoate,or “ALD”. In one embodiment, the two lactyl moieties of ALD each areracemic. Alternatively, these lactyl moieties may both have D or the Lconformations. Alternatively, one lactyl moiety may be D while the otheris L, or one may be D, L while the other is D or L. Such changes instereochemistry may improve the physical and/or biological properties ofthe resulting polymer.

In one embodiment, the adduct of an isocyanate is selected from ahexamethylene diisocyanate trimer (DESMODUR N-3390) and a hexamethylenediisocyanate biuret (DESMODUR N-100) both commercially available fromBayer AG.

In one embodiment, the settable composition, which may be formed from apolymer selected from a polyurethane, a polyureaurethane, apolyetherurethane, or a polyesterurethane comprises at least onehydrolysable linkage. In one embodiment, the at least one hydrolysablelinkage is derived from glycolic acid, lactic acid, caprolactone, orp-dioxanone. In one embodiment, the at least one hydrolysable linkage isselected from the group consisting of ester, amide, anhydride andsulfonamide linkages between the ester-urethane, urethane- orureaurethane-containing groups. In one embodiment, the compositioncomprises one or more glycolyl, lactyl, or caprolactyl hydrolysableester linkages. In one embodiment, the composition comprises one or moreethylene glycol, diethylene glycol, propane diol or butane diolhydrolysable ester linkages. In one embodiment, the compositioncomprises one or more ethylene diamine, propane diamine, butane diamine,hexamethylene diamine and polyalkylene diamine hydrolysable amidelinkages. In one embodiment, the composition comprises one or morelactyl hydrolysable ester linkages and each asymmetric lactyl moietypresent in the polymer is selected from one or more of the D, the L orthe DL (racemic) stereoisomers.

The hydrolysable isocyanate based compositions are degradable at leastdue to the presence of functional groups in the polymer chain that arereadily hydrolysable under physiological conditions. Thus, the term“partially degradable” as used in the present specification encompassesthe percentage of functional groups in the polymer chain that arehydrolyzed compared to the total number of hydrolysable groups. In thiscontext, a partially degradable isocyanate based composition encompassescompositions in which, after a suitable period of time, about 75% of thehydrolysable groups are hydrolyzed. In certain embodiments, a partiallydegradable compositions is one in which about 25% to 75% (i.e., 25, 26,27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44,45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62,63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, or 75% or 25-30, 25-35,25-40, 25-45, 25-50, 25-55, 25-60, 25-65, 25-70, 30-35, 30-40, 30-45,35-50, 35-55, 35-60, 35-65, 35-70, 35-75, 40-45, 40-50, 40-55, 40-60,40-65, 40-70, 40-75, 45-50, 45-55, 45-60, 45-65, 45-70, 45-75, 50-55,50-60, 50-65, 50-70, 50-75, 55-60, 55-65, 55-70, 55-75, 60-65, 60-70,60-75, 65-70, 65-75, or 70-75%) or 50% to 75% (i.e., 50, 51, 52, 53, 54,55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72,73, 74, or 75% or 50-55, 50-60, 50-65, 50-70, 55-60, 55-65, 55-70,55-75, 60-65, 60-70, 60-75, 65-70, 65-75, or 70-75%) or about 75% to 90%(i.e., 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, or90% or 75-80, 75-85, 75-90, 80-85, 80-90, or 85-90%)) of thehydrolysable groups are hydrolyzed.

The rate of degradation of the compositions can be controlled in orderto provide compositions that degrade at a slower or faster rate,compared to a base composition. In general, the rate of degradation iscontrolled by varying the isocyanate and polyol/polyamine components ofthe compositions, as well as the optional chain extender componentaccording to the following parameters. In one aspect, the rate ofdegradation is controlled by choice of the isocyanate and polyol.Generally, the more hydrolysable linkages, the faster it will degradewhile less hydrolysable linkages will degrade slower. In another aspect,the rate of degradation is controlled by varying thehydrophobic/hydrophilic balance of the polyol/polyamine component.Generally, the more carbon atoms or methylene groups between thehydrolysable functions, the slower will be the hydrolysis. For example,ethylene glycol will provide a composition that hydrolyses more rapidlythan, for example, 1,3 propane diol, which in turn hydrolyses morerapidly than 1,4 butane diol. In addition, the use of hydrolysablediamines as chain extenders may increase the rate of hydrolysis. Inanother aspect, copolymers of caprolactone and glycolide hydrolyzefaster than copolymers of caprolactone and lactide and the addition ofD, L-lactide also increases the rate of hydrolysis. Thus, for example, abis-diphenyldiisocyanate bridged with a polyglycolide, apolyglycolide-co- lactide, a polylactide, apolycaprolactone-co-glycolide, a polycaprolactone-co-lactide, apolycaprolactone will hydrolyze at increasingly slower rates. Forcomparison, polyurethanes prepared using methylene bis-diphenyldiisocyanate, with no hydrolyzable linkages, are notsignificantly degradable under physiological conditions. In otherembodiments, enzymatic sensitive sites such as di or polylysines orarginines are incorporated into one or more of the substituents. Inanother embodiment, the polyol or polyamine component, e.g.,hydroxymethylglycolate, may have a hydrolysable linkage to increase therate of degradation,

In one embodiment, the isocyanate component comprises a polyaromatic di-or polyisocyanate having at least one hydrolysable linkage bridging atleast two of the aromatic rings. In certain embodiments, thehydrolysable linkage bridging the aromatic rings is derived fromglycolic acid, lactic acid, caprolactone, or p-dioxanone. In most cases,the hydrolyzable linkage is an ester which may degrade into an acid andan alcohol as a result of exposure to water or to naturally occurringesterases. Amide linkages are usually more difficult to hydrolyze thanesters. Another option is the easily hydrolyzable acid anhydridelinkage. Sulfonamides may also be considered in this context. Thepolyaromatic di- or polyisocyanates described herein are distinct fromisocyantes having only a single aromatic ring such as toluenediisocyante, methylene bis-p-phenyl diisocyanate, and aromaticpolyisocyanates generally. Suitable isocyanates are described in U.S.Pat. No. 7,772,352 and U.S. Patent Application Publication No.2009/0292029, each of which is incorporated herein by reference.

In certain embodiments, the fully cured isocyanate based compositionshave a defined pore size. Porosity may be controlled through theinclusion of water, surfactants, and/or cell openers during the processof combining the one or more isocyanate components with thepolyol/polyamine component to form the isocyanate based compositions.For example, porosity may be controlled by the addition of a smallamount of water to a prepolymer containing isocyanate groups. The waterreacts with the isocyanate group to form carbon dioxide, resulting inporosity.

In one embodiment, the solid form has an average pore size in the rangeof from about 5 to 700 microns. In certain embodiments, the average poresize is from about 5 to 100 microns, from about 5 to 300 microns, fromabout 5 to 500 microns, and from about 5 to 700 microns. In certainembodiments, the average pore size is from about 100 to 300 microns,from about 200 to 500 microns, from about 300 to 600 microns, and fromabout 500 to 700 microns, or greater.

In another embodiment, the solid form has an average pore size in thesubmicron range. In certain embodiments, the average pore size is fromabout 100 to 1000 nanometers, from about 100 to 400 nanometers, fromabout 400 to 800 nanometers, from about 200 to 600 nanometers, or fromabout 500 to 900 nanometers.

Porosity may also be introduced into through the use of porous fillermaterials (e.g., commercially available calcium phosphates with poresizes of 200 microns or greater).

In one embodiment, the isocyanate based compositions are formed from anisocyanate component that comprises or consists of a glycolide-linkedpolyaromatic diisocyanate monomer and a polyol component that comprisesor consists of a polycaprolactone-co-glycolide polyol. In oneembodiment, the isocyanate based compositions are formed from a reactionthat also comprises butanediol, e.g., as a chain extender. In oneembodiment, the composition is formed from a reaction that furthercomprises one or more of water, a carboxylic acid, e.g., benzoic acid(as a foaming agent), a divalent or polyvalent metal salt, a metalcarbonate or bicarbonate, or a phosphate, e.g., for osteoconductivity.In one embodiment, the glycolide-linked diisocyanate monomer has thefollowing structure:

In one embodiment, the polycaprolactone-co-glycolide polyol has thefollowing structure:

[HOCH₂CO₂CH₂CH₂CH₂CH₂CO₂CH₂OH]n

In one embodiment, the isocyanate based compositions are formed from anisocyanate component that comprises or consists of a lactide linkeddiisocyanate monomer and a polyol component that comprises or consistsof a polycaprolactone-co-lactide polyol. In one embodiment, theisocyanate based compositions are formed from a reaction that alsocomprises butanediol, e.g., as a chain extender. In one embodiment, thecomposition is formed from a reaction that further comprises one or moreof water, a carboxylic acid, e.g., benzoic acid (as a foaming agent), adivalent or polyvalent metal salt, a metal carbonate or bicarbonate, ora phosphate, e.g., for osteoconductivity. In one embodiment, thelactide-linked diisocyanate monomer has the following structure:

In one embodiment, the polycaprolactone-co-lactide polyol has thefollowing structure:

HO[CH(CH₃)CO₂CH₂CH₂CH₂CH₂CO₂CH(CH₃)]OH_(n)

The Polyol/Polyamine Component

The diols, polyols, and polyamines suitable for use in formingabsorbable polyurethane-based compositions are either degradable ornon-degradable, or a mixture of the two. As used herein, the term“polyol” is meant to refer generically to diols and polyols, unlessindicated otherwise. Generally, absorbable isocyanate based compositionsare formed by the combination of an excess of the isocyanate componentwith the polyol/polyamine component. The relative amounts are calculatedas the molar ratio of NCO groups of the isocyanate component (I) to theactive hydrogen functional groups (H) (e.g., hydroxyl, amino, andmixtures thereof) of the polyol/polyamine component. Generally, theratio of polyisocyanate to polyol/polyamine (I:H) is at least 0.5:1. Incertain embodiments, the ratio is about 1:1, about 1.5:1, about 2:1,about 3:1, or about 4:1. In other embodiments, the ratio is about 5:1,about 8:1, about 10:1, about 20:1, or about 50:1.

In certain embodiments, the polyol/ polyamine component is present in anisocyanate prepolymer in an amount of from about 0.5% to about 50%(i.e., 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30,31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48,49, or 50% or 0.5-1, 0.5-5, 0.5-10, 0.5-15, 0.5-20, 0.5-25, 0.5-30,0.5-35, 0.5-40, 0.5-45, 5-10, 5-15, 5-20, 5-25, 5-30, 5-35, 5-40, 5-45,5-50, 10-15, 10-20, 10-25, 10-30, 10-35, 10-40, 10-45, 10-50, 15-20,15-25, 15-30, 15-35, 15-40, 15-45, 15-50, 20-25, 20-30, 20-35, 20-40,20-45, 20-50, 25-30, 25-35, 25-40, 25-45, 25-50, 30-35, 30-40, 30-45,30-50, 35-40, 35-45, 35-50, 40-45, 40-50, or 45-50%) by weight of theprepolymer. In certain embodiments, the polyol/ polyamine component ispresent in an amount of from about 0.5% to 10% (i.e. 0.5, 0.6, 0.7, 0.8,0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10% or 0.5-1, 0.5-2, 0.5-3, 0.5-4,0.5-5, 0.5-6, 0.5-7, 0.5-8, 0.5-9, 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8,1-9, 2-3, 2-4, 2-5, 2-6, 2-7, 2-8, 2-9, 2-10, 3-4, 3-5, 3-6, 3-7, 3-8,3-9, 4-5, 4-6, 4-7, 4-8, 4-9, 4-10, 5-6, 5-7, 5-8, 5-9, 5-10, 6-7, 6-8,6-9, 6-10, 7-8, 7-9, 7-10, 8-9, or 8-10%), from about 10% to 20% (i.e.,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20% or 10-15, or 15-20), fromabout 20% to 35% (i.e., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31,32, 33, 34, or 35% or 20-25, 20-30, 25-30, 25-35, or 30-35%), from about25% to 40% (i.e., 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37,38, 39, or 40% or 25-30, 25-35, 30-35, 30-40, or 35-40%), or from about35% to 50% (i.e., 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47,48, 49, or 50% or 35-40, 35-45, 40-45, 40-50, or 45-50%) by weight ofthe prepolymer.

Polyols suitable for use include biocompatible, naturally occurringpolyols, synthetic polyols, and mixtures thereof. In certainembodiments, the polyols comprise at least one ester group. In certainembodiments, the polyol comprises 2 to 4 (i.e., 2, 3, or 4) ester groupsor 5 to 10 (i.e., 5, 6, 7, 8, 9, or 10) ester groups. In one embodiment,the polyol has two or more hydroxyl groups. Suitable polyols includediols and polydiols having repeating units containing up to about 18carbon atoms. Examples of suitable diols include 1,2-ethanediol(ethylene glycol), 1,2-propanediol (propylene glycol), 1,3-propanediol,1,4-butanediol, 1,5-pentanediol, 1,3-cyclopentanediol, 1,6-hexanediol,1,8-octanediol and combinations thereof. Examples of preferred polydiolsinclude polyethylene glycol with molecular weights of from about 500 toabout 10000 (i.e., 500, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500,5000, 5500, 6000, 6500, 7000, 7500, 8000, 8500, 9000, 9500, or 10000 or500-1000, 500-5000, 1000-5000, 1000-10000, or 5000-10000),polytetramethylene ether glycols, polyols derived from glycolide,lactide, trimethylenecarbonate, p-dioxanone and/or caprolactone withmolecular weights of about 500 to about 10000(i.e., 500, 1000, 1500,2000, 2500, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 6500, 7000, 7500,8000, 8500, 9000, 9500, or 10000 or 500-1000, 500-5000, 1000-5000,1000-10000, or 5000-10000).

In one embodiment, one or more alkylpyrrolidones (see e.g., U.S. Pat.No. 7,955,616) may be added to the polyol component to improve healing.

In one embodiment, the polyol is a synthetic polyol selected from apolycaprolactone polyol, polyester polyols, polyadipate polyols (e.g.,poly(hexane-adipate) diol, poly(butane-adipate) diol,poly(ethylene/propylene-adipate) diol, poly(hexane/adipate/isophthalatediol)), and polyols that have been derived from a synthetic acid (e.g.,isophthalic acid, maleic acid). An example of a suitable biocompatiblesynthetic polyol is a polycaprolactone diol that is commerciallyavailable from Dow Chemical under the trade name TONE 32 B8. Furthernon-limiting examples of suitable synthetic polyols includepoly(oxypropylene) glycols, poly(oxytetramethylene) glycols, andpoly(oxyethylene) glycols. In one embodiment, the synthetic polyol isselected from a polycaprolactone co-glycolide or a polycaprolactoneco-lactide.

In one embodiment, the polyol is a naturally occurring polyol selectedfrom castor oil and lesquerella oil, the polyols that may be obtained bychemical modification of naturally occurring vegetable oils (e.g.,castor oil, olive oil, sesame oil, corn oil), naturally occurring oilsthat have been trans-esterified (e.g., a modified castor oil polyol thathas been prepared by the transesterification reaction of natural castoroil with suitable crosslinkers (e.g., glycerol, trimethylolpropane, andthe like) or with acids (such as adipic acid), and naturally occurringoils that have been hydrogenated. Further non-limiting examples ofsuitable naturally occurring polyols include the commercially availablecastor-oil-based polyols CASPOL5001, CASPOL1962, and CASPOL5004 (allavailable from CasChem, Inc.). In certain embodiments, the polyol is nota naturally occurring polyol such as castor oil and lesquerella oil.

In certain embodiments, an isocyanate prepolymer is combined with apolyamine to form a poly(urethane-urea). The polyamine may be a primaryor secondary di-amine, or a hindered amine. Non-limiting examples ofsuitable polyamines include, hindered diamine (e.g., isophorone diamine,“IPDA”), 1,4-cyclohexyl diamine, 1,3-pentane diamine, and aliphaticsecondary diamines, and mixtures thereof. In certain embodiments,aliphatic diamines and cycloaliphatic diamines may be particularlysuitable, and may offer improved biocompatibility. Commerciallyavailable examples of suitable polyamines include CLEARLINK 1000 (DorfKetal).

Amines including diamines that may be suitable for use in thepreparation of polyurea and polyureaurethanes include but are notlimited to polyethyleneimines, PEG amines with weight average molecularweights from about 500 to about 5,000 (i.e., 500, 1000, 1500, 2000,2500, 3000, 3500, 4000, 4500, or 5000 or 500-1000, 500-5000, or1000-5000), polyoxypropylenediamines available under the tradenameJEFFAMINES (Huntsman Corporation, Houston, Tex.) and polyetherdiaminesin general, spermine, spermidine, hexamethylenediamine,octamethylenediamine, decamethylenediamine, dodecamethylenediamine,hexadecamethylenediamine, octadecamethylenediamine, polyamidoaminedendrimers, dextrans, PEG-dextran conjugates, cysteines, proteins andpeptides containing amines, non-biologically active symmetrical andasymmetrical diamino compounds containing saturated and unsaturated,substituted and unsubstituted alkyl, aryl and alkylaryl groups havingfrom about 2 to about 18 carbon atoms. (i.e., 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, or 18 carbon atoms). Further, thediamino compound can be synthesized containing a hydrolyzable link suchas one or more ester groups to accelerate the rate of polymerdegradation (absorption) in the body. The following structureexemplifies this concept for hexamethylenediamine:H₂NCH₂CH₂CH₂COOCH₂CH₂NH₂.

In certain embodiments, the polyol comprises 2 to 4 (i.e., 2, 3, or 4)ester groups or 5 to 10 (i.e., 5, 6, 7, 8, 9, or 10) ester groups.Suitable polyols have at least two hydroxyl groups. In certainembodiments, the polyol has three or more hydroxyl groups making themcrosslinkers.

The Chain-Extender/Crosslinker Component

In certain embodiments, one or more optional chain extenders orcrosslinkers is incorporated in the formation of the absorbableisocyanate-based compositions. In certain embodiments, only a chainextender is present. In other embodiments, both a chain extender and acrosslinker are present. In one embodiment, the one or more chainextenders is a low molecular weight polyhydroxyl- and/orpolyamine-terminated compound having a molecular weight in the range of10 to 500 (i.e., 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130,140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270,280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410,420, 430, 440, 450, 460, 470, 480, 490, or 500 or 10-100, 10-200,10-300, 10-400, 100-200, 100-300, 100-400, 100-500, 200-300, 200-400,200-500, 300-400, 300-500, or 400-500) Daltons and a functionality of atleast two. In certain embodiments, the chain extender is a short-chaindiol or diamine. In a particular embodiment, the chain extender orcrosslinker is selected from glycerol, 1,4 butanediol, 1,6-hexanediol,diethylene glycol, and combinations thereof. Chain extenders having afunctionality of three or more than three are also referred to ascrosslinkers. In certain embodiments, the compositions described hereinare formed without crosslinkers and the compositions are notcrosslinked. In other embodiments, the compositions are formed with oneor more crosslinkers. The degree of crosslinking can be controlled, forexample, by varying the amount of crosslinker present.

In certain embodiments, the chain-extender or crosslinker is present inan isocyanate prepolymer in an amount in the range of about 5% to about80% (i.e., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38,39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56,57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74,75, 76, 77, 78, 79, or 80% or 5-10, 5-15, 5-20, 5-25, 5-30, 5-35, 5-40,5-45, 5-50, 5-55, 5-60, 5-65, 5-70, 5-75, 10-15, 10-20, 10-25, 10-30,10-35, 10-40, 10-45, 10-50, 10-55, 10-60, 10-65, 10-70, 10-75, 10-80,15-20, 15-25, 15-30, 15-35, 15-40, 15-45, 15-50, 15-55, 15-60, 15-65,15-70, 15-75, 15-80, 20-25, 20-30, 20-35, 20-40, 20-45, 20-50, 20-55,20-60, 20-65, 20-70, 20-75, 20-80, 25-30, 25-35, 25-40, 25-45, 25-50,25-55, 25-60, 25-65, 25-70, 25-75, 30-35, 30-40, 30-45, 30-50, 30-55,30-60, 30-65, 30-70, 30-75, 30-80, 35-40, 35-45, 35-50, 35-55, 35-60,35-65, 35-70, 35-75, 35-80, 40-45, 40-50, 45-55, 45-60, 45-65,4 5-75,45-80, 50-55, 50-60, 50-65, 50-70, 50-75, 50-80 ,55-60, 55-65, 55-70,55-75, 55-80, 60-65, 60-70, 60-75, 60-80, 65-70, 65-75, 65-80, 70-75,70-80, or 75-80%) by weight of the isocyanate prepolymer. In certainembodiments, the chain-extender or crosslinker is present in an amountof from about 5% to 20% (i.e., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, or 20% or 5-10, 5-15, 10-15, 10-20, or 15-20%), about20% to 30% (i.e., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30% or20-25 or 25-30%), about 30% to 40% (i.e., 30, 31, 32, 33, 34, 35, 36,37, 38, 39, or 40% or 30-35 or 35-40%), about 40% to 50% (i.e., 40, 41,42, 43, 44, 45, 46, 47, 48, 49, or 50% or 40-45 or 45-50%), about 50% to60% (i.e., 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60% or 50-55 or55-60%), from about 60% to 70% (i.e., 60, 61, 62, 63, 64, 65, 66, 67,68, 69, or 70% or 60-65 or 65-70%), or from about 70% to 80% (i.e., 70,71, 72, 73, 74, 75, 76, 77, 78, 79, or 80% or 70-75 or 75-80%) by weightof the isocyanate prepolymer.

The chain extender may be degradable or non-degradable. Preferably, atleast one degradable chain extender is used. Suitable degradable chainextenders for use in any of the compositions described herein aredescribed in U.S. Patent Application Serial No. 2009/0082540, which isincorporated herein by reference. In one embodiment, the at least onedegradable chain extender is HOCH₂CO₂CH₂CH₂OH or HOCH₂CO₂CH₂CH₂O₂CCH₂OH.

Other suitable chain-extenders or crosslinkers include natural orsynthetic aliphatic polyols. Suitable polydiols for use in thecompositions described herein include diol or diol repeating units withup to 8 carbon atoms. Non-limiting examples include 1,2-ethanediol(ethylene glycol), 1,2-propanediol (propylene glycol), 1,3-propanediol,1,4-butanediol, 1,5-pentanediol, 1,3-cyclopentanediol, 1,6-hexanediol,1,4-cyclohexanediol, 1,8-octanediol and combinations thereof.

In other embodiments, the chain extender is a polyol selected frompolyethylene glycol and polypropylene glycol having molecular weights of500-10000 (i.e., 500, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500,5000, 5500, 6000, 6500, 7000, 7500, 8000, 8500, 9000, 9500, or 10000 or500-1000, 500-5000, 500-10000, 1000-5000, 1000-10000, or 5000-10000)Daltons. Other examples include CASPOL1962 and CASPOL5004. In certainembodiments the preferred polydiols include polydiols selected frompolyethylene glycol and polypropylene glycol with molecular weights of500-10000 (i.e., 500, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500,5000, 5500, 6000, 6500, 7000, 7500, 8000, 8500, 9000, 9500, or 10000 or500-1000, 500-5000, 500-10000, 1000-5000, 1000-10000, or 5000-10000). Insome embodiments, the crosslinker is a non-absorbable crosslinkerselected from triethanolamine (TEA), trimethylolpropane, and QUADROL(BASF Corp.). In some embodiments, the chain-extender is anon-degradable chain extender selected from 1,4-butanediol,1,6-hexanediol, and diethylene glycol. The chain-extender or crosslinkermay be present in an isocyanate prepolymer in an amount in the range ofabout 10% to about 80% by weight of the isocyanate prepolymer.

In another embodiment, the dual putty system is able to set and adherein aqueous environments. By nature, the isocyanate component, evencontaining hydrolysable linkages, is essentially hydrophobic and willresist dissolution in aqueous systems. This is true for diamines in thiscontext. It has been found that making the diol more hydrophobic byadding a hydrophobic hydrocarbon-rich residue to a polyol, e.g.,glyceryl-1 or 2-monostearate, a more water resistant system is obtained.A variation of this embodiment involves the substitution of asilicon-based moiety for the hydrocarbon-rich residue although this mayaffect absorbability. Alternatively hydrophobicity and setting rate inaqueous environments can be improved through the use of hydrophobicfillers such as insoluble or weakly soluble aliphatic molecules andsalts thereof, including divalent salts, (e.g., calcium, magnesium, orzinc) of fatty acids. Also useful are cholesterol and its derivatives,as well as silated derivatives of ceramics or bone (Shimp et al., U.S.Pat. No. 7,270,813) Another embodiment of a water resistant, settable,dual putty system adds a small amount of hydrophobic isocyanate to therelatively hydrophilic polyol component resulting in a water-resistantmixture of polyol containing a minor amount of hydrophobic polyurethaneprepolymer. In one embodiment, the chain extender does not comprise anamino acid group.

Water

In certain embodiments, the compositions contain no added water. In someembodiments, the compositions are anhydrous. In certain embodimentswhere there is no added water, water may nevertheless be present insmall amounts. For example, certain commercially-available polyolscomprise a mixture of the polyol and a small amount of water. Inaddition, certain optional particulate materials as described herein,such as calcium carbonate may comprise bound water. Formulating thecompositions in an atmosphere that contains moisture may also result inthe incorporation of water into the compositions. In certainembodiments, the compositions are prepared under a nitrogen purge thatcomprises a desired amount of moisture, thereby controlling the watercontent of the compositions. In other embodiments, water may be added tothe compositions during the process of their formation from thecomponent parts. In other embodiments, the compositions are preparedunder essentially water-free conditions with anhydrous components suchthat the resulting compositions are essentially anhydrous.

In certain embodiments, water is present in the compositions being madein an amount from at least about 0.01% to about 3% (i.e., 0.01, 0.02,0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6,0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1,2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3% or 0.01-1, 0.01-2, 0.1-1,0.1-2, 0.1-3, 0.5-1, 0.5-2, 0.5-3, or 1-3%) by weight of thecomposition. In certain embodiments, water is present in an amount offrom about 0.05% to 1% (i.e., 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2,0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1% or 0.05-1, 0.06-1, 0.07-1,0.08-1, 0.09-1, 0.1-1, 0.2-1, 0.3-1, 0.4-1, 0.5-1, 0.6-1, 0.7-1, 0.8-1,or 0.9-1%), from about 0.05% to 1.5% (i.e., 0.05, 0.06, 0.07, 0.08,0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3,1.4, or 1.5% or 0.05-1.5, 0.06-1.5, 0.07-1.5, 0.08-1.5, 0.09-1.5,0.1-1.5, 0.2-1.5, 0.3-1.5, 0.4-1.5, 0.5-1.5, 0.6-1.5, 0.7-1.5, 0.8-1.5,or 0.9-1.5%), from about 0.1% to 1% (i.e., 0.1, 0.2, 0.3, 0.4, 0.5, 0.6,0.7, 0.8, 0.9, or 1% or 0.1-1, 0.2-1, 0.3-1, 0.4-1, 0.5-1, 0.6-1, 0.7-1,0.8-1, or 0.9-1%), from about 0.1% to 1.5% (i.e., 0.1, 0.2, 0.3, 0.4,0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, or 1.5% or 0.1-1.5,0.2-1.5, 0.3-1.5, 0.4-1.5, 0.5-1.5, 0.6-1.5, 0.7-1.5, 0.8-1.5, or0.9-1%), from about 0.1% to 2% (i.e., 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7,0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2% or0.1-2, 0.2-2, 0.3-2, 0.4-2, 0.5-2, 0.6-2, 0.7-2, 0.8-2, 0.9-2, 1.-2,1.1-2, 1.2-2, 1.3-2, 1.4-2, 1.5-2, 1.6-2, 1.7-2, 1.8-2, or 1.9-2%), fromabout 1% to 2% (i.e., 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2%or 1.1-2, 1.2-2, 1.3-2, 1.4-2, 1.5-2, 1.6-2, 1.7-2, 1.8-2, or 1.9-2%),or from about 2% to 3% (i.e., 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7,2.8, 2.9, or 3% or 2.0-3, 2.1-3, 2.2-3, 2.3-3, 2.4-3, 2.5-3, 2.6-3,2.7-3, 2.8-3, or 2.9-3%).

Particulate Materials

The settable compositions described herein may contain optionalparticulate materials. In one embodiment, the particulate material is anosteoconductive material. In certain embodiments, the particulatematerial supports or promotes the growth of bone at the applicationsite. In one embodiment, the particulate material is non-resorbable. Incertain embodiments, the mean particle size of the optional particulatematerial is in the micron or submicron range. In one embodiment, themean particle size is from about 0.001 to 0.100 microns, from about0.100 to 5 microns, from about 5 to 100 microns, from about 5 to 500microns, or from about 500 to 2000 microns.

In one embodiment, the optional particulate material is a carbonate orbicarbonate material. In one embodiment, the carbonate or bicarbonatematerial comprises or consists of one or more of calcium carbonate,magnesium carbonate, aluminum carbonate, iron carbonate, zinc carbonate,calcium bicarbonate, and sodium bicarbonate. In one embodiment, theoptional particulate material comprises or consists of bone (e.g.,demineralized bone, bone morphogenetic protein, allograft bone, and/orautogenous bone), calcium phosphate, siliconized calcium phosphate,substituted calcium phosphates (e.g., with magnesium , strontium, orsilicate), calcium pyrophosphate, hydroxyapatite, polymethylmethacrylate, glass-ionomer, absorbable phosphate glass, calciumsulfate, tricalcium phosphate (e.g., beta tricalcium phosphate), bariumsulfate, a calcium, magnesium, zinc, aluminum or barium salt of lauricacid, a calcium, magnesium, zinc, aluminum or barium salt of myristicacid; a calcium, magnesium, zinc, aluminum or barium salt of palmiticacid, a calcium, magnesium, zinc, aluminum and/or barium salt of stearicacid, a calcium, magnesium, zinc, aluminum or barium salt of arachidicacid, a calcium, magnesium, zinc, aluminum or barium salt of behenicacid, or any combination of the foregoing. Other examples include one ormore poly ether ether ketones (e.g., PEEK, REPLACE (Cortek, Inc.),EXPANCEL (Akzo Nobel)). In other embodiments, the particulate materialis a ceramic such as substituted calcium phosphates (e.g, silicate,strontium or magnesium substitution) or a glass such as bioglass. In oneembodiment, the particulate material comprises or consists of one ormore of calcium sulfate, calcium phosphosilicate, sodium phosphate,calcium aluminate, calcium phosphate, hydroxyapatite, demineralizedbone, or mineralized bone.

The optional particulate material, when present, may comprise any one ormore of the materials listed in the embodiments above. In oneembodiment, the particulate material, if present in the composition,does not comprise calcium carbonate. In one embodiment, the particulatematerial may be polymeric such as a polyurethane.

In one embodiment, the particulate material is present in an amount offrom about 0.01% to about 10% (i.e., 0.01, 0.02, 0.03, 0.04, 0.05, 0.06,0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1,1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5,2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0,4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4,5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8,6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2,8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6,9.7, 9.8, 9.9, or 10% or 0.01-1, 0.01-2, 0.01-3, 0.01-4, 0.01-5, 0.01-6,0.01-7, 0.01-8, 0.01-9, 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 2-3,2-4, 2-5, 2-6, 2-7, 2-8, 2-9, 2-10, 3-4, 3-5, 3-6, 3-7, 3-8, 3-9, 4-5,4-6, 4-7, 4-8, 4-9, 4-10, 5-6, 5-7, 5-8, 5-9, 5-10, 6-7, 6-8, 6-9, 6-10,7-8, 7-9, 7-10, 8-9, 8-10, or 9-10%) by weight of the composition. Incertain embodiments, the optional particulate material is present in anamount of 0.10% to 10% (i.e., 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8,0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3,2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8,3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2,5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6,6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0,8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4,9.5, 9.6, 9.7, 9.8, 9.9, or 10% or 0.1-1, 0.1-2, 0.1-3, 0.1-4, 0.1-5,0.1-6, 0.1-7, 0.1-8, 0.1-9, 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 2-3,2-4, 2-5, 2-6, 2-7, 2-8, 2-9, 2-10, 3-4, 3-5, 3-6, 3-7, 3-8, 3-9, 4-5,4-6, 4-7, 4-8, 4-9, 4-10, 5-6, 5-7, 5-8, 5-9, 5-10, 6-7, 6-8, 6-9, 6-10,7-8, 7-9, 7-10, 8-9, 8-10, or 9-10%), 1% to 10% (i.e., 1, 1.1, 1.2, 1.3,1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7,2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2,4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6,5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0,7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4,8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8,9.9, or 10% or 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 2-3, 2-4, 2-5,2-6, 2-7, 2-8, 2-9, 2-10, 3-4, 3-5, 3-6, 37, 3-8, 3-9, 4-5, 4-6, 4-7,4-8, 4-9, 4-10, 5-6, 5-7, 5-8, 5-9, 5-10, 6-7, 6-8, 6-9, 6-10, 7-8, 7-9,7-10, 8-9, 8-10 or 9-10%) , or 5% to 10% (i.e., 5.0, 5.1, 5.2, 5.3, 5.4,5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8,6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2,8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6,9.7, 9.8, 9.9, or 10% or 5-6, 5-7, 5-8, 5-9, 6-7, 6-8, 6-9, 6-10, 7-8,7-9, 7-10, 8-9, 8-10, or 9-10%) . In other embodiments, the optionalparticulate material is present in an amount of from about 10% to about20% (i.e., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20% or 10-15 or15-20%) by weight of the composition, or from about 20% to 30% (i.e.,20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30% or 20-25 or 25-30%),about 30% to 40% (i.e., 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40%or 30-35 or 40-45%), about 40% to 50% (i.e., 40, 41, 42, 43, 44, 45, 46,47, 48, 49, or 50% or 40-45 or 45-50%), about 50% to 60% (i.e., 50, 51,52, 53, 54, 55, 56, 57, 58, 59, or 60% or 50-55 or 55-60%), about 60% to70% (i.e., 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or 70% or 60-65 or65-70%) or about 70% to 80% (i.e., 70, 71, 72, 73, 74, 75, 76, 77, 78,79, or 80% or 70-75 or 75-80%) by weight of the composition.

In one embodiment, the particulate additive material is graphene(available from Applied Graphene Materials and Thomas Swan, Ltd.), asingle atomic layer of graphite that is electrically conductive, highlyelastic, is about 100 times stronger than steel and which may be ofvalue improving the quality of tissue healing and new bone stimulation.

Other Optional Additives

The compositions may also optionally comprise one or more “cellopeners.” Non-limiting examples include ORTOGEL501 (Goldschmidt) (ananti-foaming additive) and X-AIR (Specialty Polymers & Services). Incertain embodiments, the cell openers are present in an amount in offrom about 0.1% to 5% (i.e., 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8,0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3,2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8,3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or 5% or 0.1-1,0.1-2, 0.1-3, 0.1-4, 1-3, 1-4, 1-5, 2-4, 2-5, or 1-2, 1-3, 1-4, 1-5,2-3, 2-4, 2-5, 3-4, 3-5, or 4-5%) by weight of the composition. In oneembodiment, the cell openers are present in an amount in of from about1% to 2% or 1% to 3% by weight of the composition. Optional additivescan be added to the magnesium based section but for themalonate/cyanoacrylate section, no active hydrogen atoms can be presentincluding those in water because they will initiate polymerization.

The compositions may also optionally comprise one or more therapeuticagents. In one embodiment, the one or more therapeutic agents areselected from an anti-cancer agent, an antimicrobial agent, anantibiotic, a local anesthetic or analgesic, a statin and ananti-inflammatory agent. In one embodiment, the antibiotic is selectedfrom a broad spectrum antibiotic, such as gentamicin, clindamycin, anderythromycin, or a gram positive and gram negative family antibioticsuch as an ampicillin and a cephalosporin. In one embodiment, the localanesthetic or analgesic is selected from lidocaine, bupivacaine,tetracaine, and ropivacaine. In one embodiment, the local anesthetic oranalgesic is selected from lidocaine, benzocaine and fentanyl (a potentnon-opioid anesthetic). In one embodiment, the one or moreanti-inflammatory substances is selected from a non-specificanti-inflammatory such as ibuprofen and aspirin, or a COX-2 specificinhibitor such as rofecoxib and celeboxib.

In one embodiment, component A is a putty comprised of a concentratedaqueous solution of a polyanionic polymer, e.g., carboxymethylcellulose,and component B is a putty comprised of a concentrated aqueous solutionof a polycationic polymer. e.g., chitosan, either of which may beoptionally crosslinked. The combined materials are hemostatic whenapplied to a bleeding surface.

In one embodiment, the compositions further comprise one or more of anantioxidant, a colorant, a steroid, calcium stearate, tocopherylacetate, and triacetin. In one embodiment, the antioxidant is selectedfrom IRGANOX 1010 and IRGANOX 1035 (Ciba Geigy), and CYANOX 1790 andCYANOX 2777 (Cytec Industries). In certain embodiments, the antioxidantis present in an amount of from about 0.01% to 0.5% (i.e., 0.01, 0.02,0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, or 0.5% or0.01-0.1, 0.01-0.2, 0.01-0.3, 0.01-0.4, 0.01-0.5, 0.1-0.2, 0.1-0.3,0.1-0.4, 0.1-0.5, 0.2-0.3, 0.3-0.4, 0.3-0.5,or 0.4-0.5%) by weight ofthe composition. In one embodiment, the composition comprises one ormore of calcium stearate, tocopheryl acetate, and triacetin, eachpresent in a component putty of the composition in an amount rangingfrom 0.1 to 5% (i.e., 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1,1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4,2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9,4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or 5% or 0.1-1, 0.1-2,0.1-3, 0.1-4, 1-2, 1-3, 1-4, 1-5, 2-3, 2-4, 2-5, 3-4, 3-5, or 4-5%)based upon the weight of the component putty. Non-limiting examples ofcolorants that may be included in the compositions are gentian violet,D&C Violet #2, and D&C Green #6.

In one embodiment, the steroid is a steroid-based compound, such as anintracellular messenger, effective to modulate the rate of tissuegrowth, including bone growth.

In one embodiment, the compositions further comprise one or more growthfactors, for example BMP-2, BMP-7, PDGF, EGF, etc.

EXAMPLES Example 1: Formulations with Radiopaque Particular Component

Described herein is a study showing the effect of adding a radiopaqueparticulate component barium sulfate to a flowable paste formulation.The study described herein showed that the presence of barium sulfateincreases radiopacity of the final flowable paste composition, asdescribed herein. The radiopacity of the final flowable pastecomposition, as described herein, is a consequence of the combination ofcalcium phosphate and barium sulfate. While barium sulfate is moreradiodense than calcium phosphate, a minimum amount of barium sulfate isdesired because it does not have the same level of bone healing benefitslike calcium phosphate. The study described herein showed that theaddition of barium sulfate (BS) increased the radiodensity (lowergrayscale value ∞ higher density) over the baseline device (withoutbarium sulfate) so that it approached/exceeded the density ofconventional bone cements (Palacos R) (Table 1).

TABLE 1 Final composition (% by weight of barium sulfate (BS) Mean infinal Grayscale composition) value   1% BS 111 2.5% BS 108   5% BS 103 10% BS 91 Palacos R 103 Flowable 112 (M)

The radiopacity of the final composition is important because it allowedfor visualization in thin layers or small volumes. The final compositioncould be applied in thin layers between bone surfaces or throughcannulated/fenestrated screw, and could be differentiated from the boneand metal, which are also radiopaque, as the desired benefit (FIG.1A-1B). The results described herein showed that the exemplary flowablepaste formulation comprising barium sulfate and calcium phosphate in theconcentration ranges disclosed herein, displayed the desired radiopacitywith the bone healing properties.

Equivalents

Those skilled in the art will recognize or be able to ascertain using nomore than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed by the following claims.

All references cited herein are incorporated herein by reference intheir entirety and for all purposes to the same extent as if eachindividual publication or patent or patent application was specificallyand individually indicated to be incorporated by reference in itsentirety for all purposes.

The present invention is not to be limited in scope by the specificembodiments described herein. Indeed, various modifications of theinvention in addition to those described herein will become apparent tothose skilled in the art from the foregoing description and accompanyingfigures. Such modifications are intended to fall within the scope of theappended claims.

Unless indicated otherwise, all percentages by are percentages byweight, parts are parts by weight, temperature is in degrees Celsius,and pressure is at or near atmospheric. There are numerous variationsand combinations of reaction conditions, e.g., component concentrations,desired solvents, solvent mixtures, temperatures, pressures and otherreaction ranges and conditions that can be used to optimize the productpurity and yield obtained from the described process. Only reasonableand routine experimentation will be required to optimize such processconditions.

1. A bone hemostatic and adhesive composition comprising a first component and a second component, wherein the first component comprises 30% to 40% of a polyfunctional isocyanate compound, less than 0.5% of one or more polyols, 50% to 65% of a particulate component, based upon the total weight of the first component, wherein the second component comprises 3% to 5% of a polyfunctional isocyanate compound, 0.5 to 15% of one or more polyols, 70% to 85% of a particulate component, based upon the total weight of the second component, wherein the particulate component comprises one or more particulate materials, and wherein the first and the second components are mixed together to form a bioabsorbable, homogenous composition.
 2. The composition of claim 1, wherein the first component comprises 35% to 40% of a polyfunctional isocyanate compound, based upon the total weight of the first component, and wherein the second component comprises 3% to 5% of a polyfunctional isocyanate compound, based upon the total weight of the second component.
 3. The composition of claim 1, wherein the first component comprises less than 0.5% of one or more polyols, based upon the total weight of the first component, and wherein the second component comprises 2% to 10% of one or more polyols, based upon the total weight of the second component.
 4. The composition of claim 1, wherein the first component comprises less than 0.5% of one or more polyols, based upon the total weight of the first component, and wherein the second component comprises 10% to 15% of one or more polyols, based upon the total weight of the second component.
 5. The composition of claim 1, wherein the first component comprises 50% to 55% of a particulate component, based upon the total weight of the first component, and wherein the second component comprises 70% to 75% of a particulate component, based upon the total weight of the second component.
 6. The composition of claim 1, wherein the homogenous composition formed by mixing the first and the second component, comprises 50% to 75% of a particulate component, based upon the total weight of the homogenous composition.
 7. The composition of claim 1, wherein the homogenous composition comprises about 0.1% to about 5% of one or more additives, based upon the total weight of the homogenous composition.
 8. The composition of claim 1, wherein the homogenous composition comprises about 0.9% to about 5% of one or more additives, based upon the total weight of the homogenous composition.
 9. The composition of claim 1, wherein the homogenous composition comprises about 1% to about 5% of one or more additives, based upon the total weight of the homogenous composition
 10. The composition of claim 1, wherein the polyfunctional isocyanate compound is aromatic isocyanate, an aliphatic isocyanate, a cycloaliphatic isocyanate, and an adduct of an isocyanate.
 11. The composition of claim 1, wherein the polyfunctional isocyanate compound is any one of an absorbable lactide diester (ALD), ethyl lysine diisocyanate, cyclohexyl diisocyanate, hexamethylene diisocyanate, a hexamethylene diisocyanate trimer, a hexamethylene diisocyanate biuret, a methylene bis- diphenyldiisocyanate, a lysine diisocyanate, a diphenylmethanediisocyanate (MDI), 4,4-diphenylmethanediisocyanate, a mixture of 2,4′-diphenylmethanediisocyanate and 4,4′-diphenylmethanediisocyanate isomers, a polycarbodiimide-modified diphenylmethane disocyanate, polymethylene polyphenylisocyanate.
 12. The composition of claim 1, wherein the polyfunctional isocyanate compound is an absorbable lactide diester (ALD).
 13. The composition of claim 1, wherein the one or more polyols is any one of ethylene glycol, diethylene glycol, propanediol, 1,2-propanediol (propylene glycol), 1,3-propanediol, 1,2-ethanediol (ethylene glycol), butanediol, 1,4-butanediol, 1,5-pentanediol, 1,3-cyclopentanediol, 1,6-hexanediol, 1,8-octanediol, polytetramethylene ether glycols, polyols derived from glycolide, lactide, trimethylenecarbonate, p-dioxanone, polycaprolactone triol, polycaprolactone polyol, polyester polyol, polyadipate polyol, diol, poly(butane-adipate) diol, poly(ethylene/propylene-adipate) diol, poly(hexane/adipate/isophthalate diol)), poly(oxypropylene) glycol, poly(oxytetramethylene) glycol, and poly(oxyethylene) glycols, polycaprolactone co-glycolide, a polycaprolactone co-lactide or triethanolamine (TEOA) or a combination thereof.
 14. The composition of claim 1, wherein the one or more polyols is a polycaprolactone triol, a butanediol, a triethanolamine or a combination thereof.
 15. The composition of claim 1, wherein the particulate component is calcium phosphate, siliconized calcium phosphate, substituted calcium phosphates, calcium pyrophosphate, calcium stearate, barium sulfate, a calcium, magnesium, zinc, aluminum or barium salt of lauric acid, a calcium, magnesium, zinc, aluminum or barium salt of myristic acid; a calcium, magnesium, zinc, aluminum or barium salt of palmitic acid, a calcium, magnesium, zinc, aluminum and/or barium salt of stearic acid, a calcium, magnesium, zinc, aluminum or barium salt of arachidic acid, a calcium, magnesium, zinc, aluminum or barium salt of behenic acid, polyethylene glycol (PEG) laurate, PEG stearate, PEG palmitate, PEG behenate, hydroxyapatite, polymethyl methacrylate, glass-ionomer, absorbable phosphate glass, calcium sulfate, tricalcium phosphate, calcium carbonate, magnesium carbonate, aluminum carbonate, iron carbonate, zinc carbonate, calcium bicarbonate, sodium bicarbonate, demineralized bone, or mineralized bone, or a combination thereof.
 16. The composition of claim 1, wherein the particulate material is calcium phosphate, calcium stearate or a combination thereof.
 17. The composition of claim 1, wherein the particulate component of the first component comprises 0% to 1% of calcium stearate, and 53% to 62% of calcium phosphate, based upon the total weight of the first component, and the particulate component of the second component comprises 0.1 to 0.5% of calcium stearate, and 70% to 84% of calcium phosphate, based upon the total weight of the second component.
 18. The composition of claim 17, wherein the homogenous composition formed by mixing the first and the second component, comprises 0.2% to 1% of calcium stearate, and 56% to 73% of calcium phosphate, based upon the total weight of the homogenous composition.
 19. The composition of claim 1, wherein the particulate material comprises barium sulfate, calcium stearate, calcium phosphate or a combination thereof.
 20. The composition of claim 19, wherein the particulate material of the first component comprises 1% to 10% of barium sulfate, 1% to 2% of calcium stearate and 48% to 53% of calcium phosphate, based upon the total weight of the first component, and the second component comprises 0.1% to 0.5% of calcium stearate and 70% to 75% of calcium phosphate, based upon the total weight of the second component.
 21. The composition of claim 20, wherein the homogenous composition formed by mixing the first and the second component, comprises 0.5% to 8.5% of barium sulfate, 0.2% to 1% of calcium stearate and 50% to 65% of calcium phosphate based on the weight of the homogenous composition.
 22. The composition of claim 1, wherein the one or more additives is any one of an antioxidant, a colorant, a steroid, tocopheryl acetate, or triacetin or a combination thereof.
 23. The composition of claim 1, wherein the first component comprises 0% of triacetin, based upon the total weight of the first component, and the second component comprises about 0.5% to about 2% of triacetin, based upon the total weight of the second component.
 24. The composition of claim 23, wherein the homogenous composition formed by mixing the first and the second components, comprises about 0.1% to about 1% triacetin, based upon the total weight of the homogenous composition.
 25. The composition of claim 1, wherein the first component comprises about 6% to about 7% of tocopheryl acetate, based upon the total weight of the first component, and the second component comprises about 0% to about 4% of tocopheryl acetate, based upon the total weight of the second component.
 26. The composition of claim 25, wherein the homogenous composition formed by mixing the first and the second components, comprises about 5% to about 6% of tocopheryl acetate, based upon the total weight of the homogenous composition.
 27. The composition of claim 1, wherein the homogenous composition formed by mixing the first and the second components, comprises 20% to 40% of a polyurethane copolymer, based upon the total weight of the homogenous composition.
 28. The composition of claim 27, wherein the homogenous composition comprises a polyurethane co-polymer comprising of an Absorbable Lactide Diester (ALD)-Polycaprolactone Triol (PCL)-Butanediol (BDO)-Triethanolamine (TEOA) polymer (ALD-PCL-BDO-TEOA polymer).
 29. The composition of claim 1, wherein the homogenous composition formed by mixing the first and the second components is moldable or hand-settable.
 30. The composition of claim 1, wherein the first component, the second component and the homogenous composition formed by mixing the first and the second components are a paste.
 31. The composition of claim 30, wherein the homogenous composition formed by mixing the first and the second components is a flowable paste.
 32. The composition of claim 1, wherein the homogenous composition formed by mixing the first and the second components cures into a hardened composition, in a time period of between 1 minute to 30 minutes.
 33. The composition of claim 1, wherein the homogenous composition formed by mixing the first and the second components cures into a hardened composition, in a time period of between 6 hours to 24 hours.
 34. A cannulated bone screw having a shaft, a tip, and a head, at least a portion of said shaft having threads thereon configured to be inserted into a bone, wherein the screw comprises a cannulation along the shaft comprising an amount of the homogenous composition of claim 1 within the cannulation, and at least one fenestration disposed along the shaft of the screw and connected to the cannulation of the screw, wherein the fenestration allows the composition to pass through the at least one fenestration of the screw into a bone.
 35. The cannulated bone screw of claim 34, wherein the bone screw is configured for insertion into a hole drilled in a bone.
 36. The cannulated bone screw of claim 35, wherein the bone screw is configured for securing in the hole drilled in a bone by an amount of the composition of claim 1 that is in contact with the outer surface of the screw and the walls of the hole.
 37. The cannulated bone screw of claim 34, wherein the bone screw further comprises central opening in the outer end of the head of the screw configured to for receiving a driving tool for driving the screw into the bone, and for receiving the homogenous composition.
 38. A method of delivering a bone hemostatic and adhesive composition into a site in a bone of a patient in need thereof, the method comprising: a) providing the cannulated bone screw of claim 34; b) inserting the cannulated bone screw into the bone of the patient; and c) allowing the amount of the composition within the bone screw to be delivered into the bone.
 39. The composition of claim 1, for use in a method of securing a surgical hardware into a bone of a subject in need thereof, wherein the surgical hardware has a body and an opening at a point of the body, wherein the surgical hardware is cannulated inside the body of the hardware, and comprises at least one fenestration along the body of the hardware for receiving the composition, wherein the method comprises: a) inserting the surgical hardware into a site on the bone; b) delivering the composition hardware inside through the opening into the cannulation in the body of the surgical hardware; c) allowing the composition to pass through the fenestration of the surgical hardware into an area surrounding the hardware in the bone; and d) allowing the composition to harden to secure the surgical hardware to the bone.
 40. The composition of claim 39, wherein the surgical hardware is a screw, a plate, a mesh, a wire, a rod or a nail or equivalent thereof. 